The synthesis of fluorescent DNA intercalator precursors through efficient multiple heck reactions

Article abstract of DOI:10.1071/CH10374

A highly efficient synthesis of p-carboethoxy-tristyryl and carboethoxy-terastyrenyl benzene derivatives through a multiple Heck cross coupling reaction is reported. This reaction provides an efficient route to DNA intercalator precursors containing a benzene core. CSIRO 2011.

Full text of DOI:10.1071/CH10374

Full Paper
CSIRO PUBLISHING
Aust. J. Chem. 2011, 64, 316–323
www.publish.csiro.au/journals/ajc
The Synthesis of Fluorescent DNA Intercalator Precursors
through Efficient Multiple Heck Reactions
A
A
A
C
Nigel A. Lengkeek, Ramiz A. Boulos, Allan J. McKinley, Thomas V. Riley,
B
A D
,
Boris Martinac, and Scott G. Stewart
A
M313, Chemistry, School of Biomedical, Biomolecular and Chemical Science,
University of Western Australia, 35 Stirling Highway, Crawley, WA, 6009, Australia.
Victor Chang Cardiac Research Institute, Lowy Packer Building, 405 Liverpool Street,
Darlinghurst, Sydney, NSW 2010, Australia.
B
C
M502, Microbiology and Immunology, School of Biomedical, Biomolecular
and Chemical Sciences, The University of Western Australia,
35 Stirling Hwy, Nedlands, WA 6009, Australia.
D
Corresponding author. Email: sgs@cyllene.uwa.edu.au
A highly efficient synthesis of p-carboethoxy-tristyryl and carboethoxy-terastyrenyl benzene derivatives through a
multiple Heck cross coupling reaction is reported. This reaction provides an efficient route to DNA intercalator precursors
containing a benzene core.
Manuscript received: 21 October 2010.
Manuscript accepted: 10 January 2011.
Introduction
HO2C
Organic based DNA intercalators represent a variety of func-
tionalized aromatic compounds from the straightforward acri-
dine dye Proflavine (1, Fig. 1) to the more complex ligands
such as the anthraquinone based natural product daunomycin
(2). Most organic DNA intercalators have a variety of functional
groups attached to the aromatic scaffold, many of which are
normally vital to the activity and stability of the drug-DNA
complex. For instance in the anthracyclines (i.e. daunomycin 2)
an electron deficient quinone system is needed to interact with
the electron rich base pairs but the C9 hydroxyl moiety is con-
sidered the pharmocophore responsible for the drugs any anti-
cancer activity.[1] Our interest in fluorescent DNA intercalators
has initially been devised around medium-sized styryl com-
pounds bearing a central benzene core (3–7). In designing the
styryl ring system it was presumed these systems would be
slightly less rigid than more traditional intercalators, but have
similar p-stacking interactions. Many intercalators contain an
amine at the periphery (as an ammonium cation at pH 7) which
binds with the phosphate group of the DNA. In our system
terminal and conjugated carboxylic acids were targeted, a
functionality which was considered versatile enough to quickly
access other functional groups such as amines, amides and
phenols. An eventual objective was to provide derivatives that
could dramatically alter their fluorescence profile on interaction
with DNA.[2] Compounds of this type have also been examined
for their use as optical brightening (OBAs) or optical bleaching
agents.[3]
H2N
NH2
CH3
N
1
OH
CO2H
O
O
OH
OCH3O
OH
O
O
CH3
OH
3
4
2
NH2
CO2H
HO2C
CO2H
HO2C
CO2H
5
CO2H
HO2C
CO2H
CO2H
HO2C
HO2C
CO2H
Reported literature preparation of such compounds normally
involve a Wittig based approach in which the central fragment
comes from either a di- or tri-benzaldehyde or the reverse where
a central stabilized Horner-Wodsworth-Emmons phosphonate
6
7
Fig. 1. Known DNA intercalators proflavine (1) and daunomycin (2) as
well as proposed DNA intercalators precursors (3–7).
Ó CSIRO 2011
10.1071/CH10374
0004-9425/11/030316

Synthesis of Fluorescent DNA Intercalator Precursors
317
Br
Br
Br
Br
Br
Br
Br
ꢀ
ꢀ
ꢀ
CO2Et
CO2Et
CO2R
CO2Et
Br
Br
Br
8
9
13
9
17
9
(a)
(a)
(a)
RO2C
RO2C
CO2R
CO2R
CO2R
RO2C
CO2R
14–R ꢁ Et
6–R ꢁ H
18–R ꢁ Et
7–R ꢁ H
b
(b)
RO2C
CO2R
(c) (from 14)
(c) (from 18)
10–R ꢁ Et
5–R ꢁ H
(b)
CO2R
CO2R
RO2C
RO2C
CO2R
CO2R
(c) (from 10)
CO2R
RO2C
15–R ꢁ Et
16–R ꢁ H
19–R ꢁ Et
20–R ꢁ H
(d)
(d)
RO2C
CO2R
11–R ꢁ Et
12–R ꢁ H
(d)
Scheme 1. The synthesis of the target compounds through Heck cross coupling approach. Reagents and conditions: (a) Pd2(dba)3/[(t-Bu)3PH]BF4, THF,
reflux, 17 h (82–97%). (b) LiOH, H2O/EtOH, reflux, 3 h. (c) Pd/C-H2, CH2Cl2/EtOH, 17 h. (d) LiOH, H2O/EtOH, reflux, 3 h.
Table 1. Trials of the Heck cross coupling reaction between 1,3,5-tribromobenzene (8) and ethyl 4-vinylbenzoate (9)
Entry
Catalyst
Mol-% catA
Base/additive
Solvent
Temp [8C]
Time
Yield of 8 [%]
1
2
3
4
5
6
7
8
9
Pd(OAc)2
Pd(OAc)2
5
5
K2CO3
DMF
100
111
100
100
111
100
111
70
2 d
2 d
6 d
2 d
3 d
3 d
2 d
5 d
14 h
0
K2CO3
Toluene
0
B
Pd(OAc)2
2
K2CO3/NBu4Br
Et3N
DMF
3
Pd(OAc)2/PPh3
HB PCC
HB PCC
5
DMF
0
10
10
5
NBu4OAc
NBu4OAc
K2CO3
Toluene
0
DMF/MeCN/H2O (5:5:1)
TraceD
Pd(PPh3)4
Toluene
THF
0
0
Pd(PPh3)4
10
15
Cy2MeN
Cy2MeN
Pd2(dba)3/t-Bu3P
THF
70
97
AMol-% catalyst per Heck reaction.
BJeffery’s conditions.[15]
CHB PC: Hermann-Beller Palladacycle.[11]
DBased on TLC analysis against isolated material.
ester isused. In many cases these processesare eitherlowyielding
or the procedure provides a mixture of E and Z-geometrical
isomers at each tether.[4–7] Furthermore, for the purposes of
producing reasonable quantities of a precursor olefin, the addi-
tional steps of providing a tri or tetra-phosphonate ester maybe
time consuming and problematic. Recently, the group of Sinha
has developed a domino based approach to these systems which
results in good yields of the bis-arylated systems but this process
may not be amenable to our benzyl esters/benzoic acids.[8]
The Heck reaction provides a high yielding and E-selective
approach to such unsaturated systems[9–11] Pioneering work
by de-Meijere has provided a method for the construction of
tri and tetra-styrene benzene derivatives through a tandem
Heck approach using Jefferey’s phosphine free conditions
(Pd(OAc)2, NBu4Br, K2CO3, DMF)[12] while others have inves-
tigated dihalogenated systems in reasonable yields where the
styrene coupling partner is substituted.[7,13,14] In this paper we
plan to investigate the Heck cross coupling approach to various
di-, tri- and tetra-styrenyl tethered benzene based compounds as
precursors to our target compounds (3–7).
Results and Discussion
Initial strategies to follow the preparation of tristyrene 10
(Scheme 1) through a Wittig based approach, with 1,3,5-
tribenzaldehyde were problematic.[4] Following these setbacks
we investigated a Heck cross coupling based approach from the
commercially available 1,3,5-tribomobenzene (8) and ethyl-40-
vinylbenzoate (9). It was assumed that following the first Heck

318
N. A. Lengkeek et al.
Table 2. Heck cross coupling between ethyl 4-vinylbenzoate 9 and
various halobenzenes employing the Pd2(dba)3/t-Bu3P catalytic system
Entry Substrate Mol-% catalystA Time [h] Product Yield [%]
1
2
3
4
5
8
13
17
26
27
15
2
14
15
15
18
72
10
14
18
28
28
97
88
82
84
29
5
5
5
AMol-% catalyst per Heck reaction.
Fig. 2. Fluorescence of compounds 28, 10, 14 and 18 (left to right) in
CH2Cl2 at 1 ꢀ 10ꢁ7 M irradiated at 364 nm.
reaction the aromatic ring would be considered less electron rich
improving the rate of oxidative addition for the second Heck
reaction thus improving the chances of a multiple or tandem type
process.[15] Initial attempts using Pd(OAc)2 or Jeffery’s phos-
phine free conditions (Table 1) unfortunately led to either none
or only small amounts of the desired trisubstituted product 10
being isolated (Entries 1 to 3).[16] While some of the above
mentioned conditions showed initial promise (Entries 3 and 6)
small alterations to these conditions did not improve the overall
yield.
Absorbance
Fluorescence
CH2Cl2
Cyclohexane
Trials using the thermally stable palladacycle, popularized by
Hermann and Beller, using toluene were not successful and
trace amounts of the desired product were realized under specific
solvent conditions (DMF/MeCN/H2O, Entry 6).[13,17,18] Since
similar synthetic transformations with matching catalytic condi-
tions have been reported in a range of yields[13,19–21] it is assumed
that the specific electronic nature of our coupling partner plays a
large role in these observed lowyields. Fortunately vast improve-
ments in yield were finally realized with the use of the Pd2(dba)3
and P(t-Bu)3 catalytic system.[22] Remarkably even at lower
temperatures this successful catalytic system was highly effec-
tive for the multiple process.
250
300
350
400
450
500
Wavelength [nm]
As discussed earlier, despite the potential for numerous
products as a result of incomplete alkenylation or dehalogena-
tion,[10] we were still surprised to observe only the fully
olefinated products. With these factors considered, in our hands
this trihalogenalted system the Heck reaction provides a far
more attractive route compared with the Wittig based approach
from the unstable 1,3,5-tribenzaldehyde which is amenable to
scale up.[4]
Fig. 3. Normalized UV-Vis and fluorescence spectra of 10 in CH2Cl2
(excitation at 330 nm) and cyclohexane (excitation at 328 nm).
chromatography. In
a further comparison of synthetic
approaches, the synthesis of 25 was examined using both the
Wittig and Heck procedures (Scheme 2).[23]
General Reaction Conditions: Halogenated benzene
(1 equiv.), ethyl 4-vinylbenzoate 9 (1.1 equiv. per halogen),
Pd2(dba)3/[(t-Bu)3PH]BF4, THF, reflux.
The Wittig approach gave the desired dialkene 23 as a
mixture of E/E and E/Z isomers in a 40/60 ratio (44/56 ratio
for 1,3 derivative 4). The procedure adopted gave significantly
higher yields than previously observed[6,24] while the Heck
reaction equivalent gave solely an E/E isomeric mixture, 28.
As before reduction with Pd/C-H2 and saponification with LiOH
furnished the desired compound 25. Although dibenzaldehydes
are commercially available, preparation of the trialdehydes and
tetraaldehydes can be problematic while a wide array of halo-
aromatics are commercially available.[25]
Having found an effective set of catalytic conditions for the
multiple Heck reaction the Pd2(dba)3/P(t-Bu)3 system (Table 2)
was used as the key reaction to prepare the aforementioned
target compounds 3–7 (Fig. 1). As this catalyst has also been
shown to be effective with aryl chlorides,[22] trials with 1,4-
dichlorobenzene were also attempted. Unfortunately, even at
extended reaction times the yields (Entry 5) were considerably
lower. While some reduction in catalyst loading was investi-
gated, 2% per Heck reaction, further reductions may be possible,
but remain to be investigated. As previously, the crude NMR
spectra showed no signs of halogenated precursors or the Z-
geometric isomer. As highlighted in Schemes 1 and 2, the
approaches to the targets containing di-, tri- and tetra-tethers
is identical. Since we sought to investigate the role of extended
conjugation in DNA intercalation we also required the reduced
derivatives. Hydrogentaion of the alkenes (Schemes 1 and 2)
with 10% Pd/C in a hydrogen atmosphere proceeded well (79–
98%), as did subsequent saponification (LiOH, 85–95% yield).
In the unsaturated series of compounds (alkene tethered car-
boxylic acid derivatives 5, 6, 7, 3), the desired products were
purified by recrystallisation thus alleviating the need for
Electronic and Fluorescent Properties
Electronic and fluorescence data for specific compounds are
indicated in Table 3 for both CH2Cl2 and cyclohexane (Image 2,
Fig. 2). Comparable data for compounds from the literature,
including stilbenes,[26] styrylstilbenes[6,27] and poly(styryl)
benzenes are included (see Accessory Publication).[5,7,28] The
structure of the spectra remains relatively unchanged, except
for a small red-shift for all compounds consistent with the

Synthesis of Fluorescent DNA Intercalator Precursors
319
CO2Me
CO2Me
CO2H
CO2Et
CO2H
CHO
CHO
X
X
CHO
(a) (4), (b) (31), (c)
(a)
(b)
(c)
(f) (29), (g)
(d)
CO2Et
CO2Me
CHO
30
Bꢂrꢀ
Ph3P
21
26–X ꢁ Br
27–X ꢁ Cl
22
CO2H
32
CO2Me
23
CO2Me
24
CO2Et
CO2H
25
28–R ꢁ Et
3–R ꢁ H
(e)
Scheme 2. Reagents and conditions: (a) NaOMe, MeOH, 22, rt, 17 h, 84%. (b) Pd/C (10% w/w), H2, 1:1 CH2Cl2/MeOH, 17 h, rt, 93%. (c) LiOH, MeOH/H2O,
reflux, 17 h, 97%. (d) Pd2(dba)3ꢂCHCl3, [(t-Bu)3PH]BF4, Cy2NMe, THF, reflux, 17 h, 84% from 26, 72 h, 29% from 27. (e) LiOH, 9:1 EtOH/H2O, reflux, 17 h,
66%. (f) Pd/C, H2, 1:1 CH2Cl2/EtOH, 17 h, 96%. (g) LiOH, EtOH/H2O, reflux, 17 h, 82%.
Table 3. Electronic and fluorescence data for 10, 14, 18 and 28
Compound
Solvent
UV/Vis-l [log e]
Fluorescence (lex[lemis]) lex
lem
10
CH2Cl2
258 [4.49], 330 [4.28]
328, 341
258
328
258
334
258
336
254
369
414, 437
393, 413
436, 450
416, 440
455, 518
442
Cyclohexane
CH2Cl2
14
18
28
258 [4.53], 338 [4.83]
334, 358 s
Cyclohexane
CH2Cl2
258 [4.62], 312 [4.73], 346 [8.42]
241, 336
Cyclohexane
CH2Cl2
254 [3.85], 372 [4.74]
247, 369
414, 437
404, 428
Cyclohexane
change to more polar CH2Cl2. All the compounds have shown an
absorbance at ca 258 nm, which is consistent with a styryl B-
band transition. Surprisingly, none of the compounds show an
obvious absorbance at ca 300 nm that could correspond to a
stilbene type absorbance.
In summary, we have described a simple synthesis of di-,
tri- and tetra-phenylethyl benzene compounds containing car-
boxylic acid functional groups. This was achieved through the
development of an efficient multiple Heck cross coupling
reaction through the exploration of various palladium catalysts.
The longer wavelength absorbances are consistent with a red-
shift in the K-band absorbances due to the extended conjugation
within the compounds. These are comparable to some analogues
compiled in Table 3. While the red-shift increases from the tris-
to tetra-compounds (14 and 18) the largest observed red-shift
stilbene was in the bis-compound, suggesting the pattern of
substitution may be as important as the degree of substitution.
The fluorescence spectra of all compounds show a distinct
redshift from cyclohexane to CH2Cl2, though the structure of
the spectra remains relatively unaffected (for compound 10 see
Fig. 3). The fluorescence spectra obtained were found to be
largely independent of excitation at the B-band (,258 nm) or
the longer wavelength bands, suggesting the excited states share
a common intermediate state or the higher energy state decays
through the lower. The anisotropy may be due to the compli-
cated photochemistry of stilbenes[29] or the manifestation of
‘dual fluorescence’ commonly observed in push-pull stilbenes
such as (E)-4-dimethylamino-40-cyanostilbene (see Accessory
Publication).[26c,29] The later is unlikely as the effect is generally
eliminated in non-polar solvents, but persists in these com-
pounds. Fluorescence spectra of the tetra-substituted com-
pound, 18, show several short wavelength emissions
consistent with trans-cis isomerisation.[29a,30] The cursory
examination of the photophysical properties of these com-
pounds has revealed some interesting features and further
investigations are underway to elucidate their photophysical
properties.
Experimental
Terephthaldehyde, tributylphosphonium tetrafluoroborate,
1,3,5-tribromobenzene and 1,2,4-tribromobenzene were pur-
chased from the Sigma-Aldrich Chemical Co. Dry THF was
distilled from sodium benzophenone ketyl radical and stored
over a sodium mirror. N-Methyldicyclohexylamine was dis-
tilled under reduced pressure and stored under argon. Dess-
Martin Periodinane,[31] Herrmann-Beller paladacycle,[17a]
(methyl 4-carboxybenzyl)triphenylphosphonium bromide,[32]
[34]
Pd2(dba)3ꢂCHCl3,[33] and Pd(PPh3)4
were prepared as
described previously. 1,3-Di(hydroxymethyl)benzene was pre-
pared by the LiAlH4 reduction of dimethyl 1,3-benzenedi-
carboxylate in a similar procedure to the 1,2-isomer.[35] Ethyl
4-vinylbenzoate was prepared by the Fischer esterification of
4-vinyl benzoic acid[36a] while iso-phthalaldehyde was prepared
as via the literature.[36b]
NMR spectra were acquired on either a Bruker AV500 (1H at
500.13 MHz, 13C at 125.8 MHz) or a Bruker AV600 (1H at
600.13 MHz, 13C at 150.9 MHz) and all signals d are reported in
parts per million [ppm]. 1H and 13C assignments were made with
the aid of DEPT, COSY, HSQC and HMBC sequences where
1
appropriate. H spectra were referenced to residual (partially)
undeuterated solvents, CDCl3 (CHCl3 at 7.26 ppm) and d6-
DMSO (d5-DMSO at 2.50 ppm (pentet)). 13C spectra were
referenced to the deuterated solvents, CDCl3 at 77.16 ppm and
d6-DMSO at 39.52 ppm. Infrared spectra samples were prepared

320
N. A. Lengkeek et al.
using the KBr disc method and samples acquired on a Perkin–
Elmer Spectrum One spectrometer at 2 cmꢁ1 resolution. Elec-
tronic spectra were collected using a HP8452 spectrophotometer
in 1 cm quartz cells at ,1 ꢀ 10ꢁ5 or ,1 ꢀ 10ꢁ6 mol Lꢁ1 in the
solvents indicated. Fluorescence spectra were recorded on a
(CH2Cl2): excitation [nm] (emission [nm]) 258 [397, 418,
518], 330 [397, 418]; (cyclohexane) 328 [393, 413].
1,3,5-Tris[(1E)-20-(400-benzoic acid)vinyl]benzene (5)
Using the standard saponification procedure, 10 (252.1 mg,
0.42 mmol), LiOHꢂH2O (112.0 mg, 2.7 mmol) and 1:9 H2O/
EtOH (20 mL) gave an gelatinous precipitate that was collected
and recrystallised from THF/H2O and dried to give the triacid 5
as a pale brown powder (209 mg, 95%). 1H NMR (500.1 MHz,
d6-DMSO): d 7.49 (m, 6H, vinyl CH), 7.76 (d, J 8.5, 6H, ArH),
7.88 (s, 3H, core ArH), 7.98 (d, J 8.5, 6H, ArH); 13C NMR
(125.8 MHz, d6-DMSO): d [ppm] 125.0, 126.5, 128.4, 129.7,
129.9, 130.50, 137.6, 141.3, 167.1; IR (KBr): n [cmꢁ1] 3067,
3026, 1684 (nC¼O), 1604, 1566, 1420, 1384, 1312, 1286,
1179; HR-EIþ-MS: C33H24O6 requires 516.1573 amu, found
516.1564; EIþ-MS: MI ¼ C33H24O6; m/z: 516.1 (100%) ¼ MIþ,
472.1 (11.3%) ¼ [MI ꢁ CO2]þ.
Varian Fluorescence Spectrophotometer at 1 ꢀ 10ꢁ7 mol Lꢁ1
.
Mass spectra were acquired on a VG Autospec employing the
electron impact (EI) ionization mode.
Standard Conditions for Heck Cross Coupling Procedure
To a flame-dried schlenk flask was added the halobenzene
(1 equiv.), Pd2(dba)3ꢂCHCl3 (2–15 mol-%) and [(t-Bu)3PH]BF4
(10–60 mol-%) which were subsequently dried under vacuum
for 15 min before being dissolved in dry THF. N-Methyl-
dicyclohexylamine (4 equiv.) and ethyl 4-vinylbenzoate 7
(3.3 equiv.) were added via syringe and the reaction monitored
by TLC (neat CH2Cl2). Upon completion of the reaction the
residual THF was removed under vacuum, the crude material
redissolved in CH2Cl2 and filtered to remove any insoluble
material before being absorbed onto fine silica and eluting with
0:100 to 2:98 MeOH/CH2Cl2.
1,3,5-Tris[(1E)-20-(ethyl 400-benzoate)ethyl]benzene (11)
Conducted as per the standard reduction procedure with
trimester 10 (251 mg, 0.42), Pd/C (20 mg) and 1:1 CH2Cl2/EtOH
(15 mL). The crude product was recrystallized from CH2Cl2/
EtOH to give the triester 11 (237 mg, 93%) of a white solid.
1H-NMR (600 MHz, CDCl3): d 1.38 (t, J 7.1, 9H, CH3), 2.87
(m, 12H, bridge CH2), 4.36 (q, J 7.1, 6H, CH2), 6.76 (s, 3H),
7.20 (d, J 8.1, 6H, ArH), 7.97 (d, J 8.1, 6H, ArH); 13C NMR
(150MHz, CDCl3): d 14.4, 37.5, 38.0, 60.8, 126.5, 128.3, 128.6,
129.7, 141.4, 147.2, 166.7; HR-EI-MS: C39H42O6 requires
606.2981 amu, found 606.2994.
Standard Method for Reduction of Alkenes
The alkene was loaded into a glass autoclave tube and dissolved/
suspended in 1:1 CH2Cl2/MeOH or 1:1 CH2Cl2/EtOH depend-
ing upon the ester present. Argon was bubbled through the
mixture for 10 min before 10% Pd/C (,10 wt-% of alkene) was
added, and the flask pressurized with H2 (50 atm). The reaction
was allowed to proceed for 17 h before being depressurized,
purged with argon, filtered through a pad of celite and con-
centrated under reduced pressure. Further purification is
described for each compound when necessary.
1,3,5-Tris[20-(400-benzoic acid)ethyl]benzene (12)
Using the standard procedure triester 11 (252.0 mg,
0.42 mmol), LiOHꢂH2O (107.2 mg, 2.6 mmol) and 1:9 H2O/
EtOH (20 mL) gave triacid 3 (202 mg, 93%) as a white powder.
1H-NMR (500 MHz, d6-DMSO): d 2.82 (cm, 12H, CH2), 6.83 (s,
3H, ArH), 7.28 (d, J 8.2, 6H, ArH), 7.85 (d, J 8.2, 6H, ArH); 13C
NMR (125 MHz, CDCl3): d 36.7, 37.1, 126.2, 128.4, 126.2,
129.3, 140.9, 146.9, 167.3; IR (KBr): n [cmꢁ1] 3067, 2929,
1686, 1610, 1422, 1315, 1288, 1179; HR-FAB-MS: C33H31O6
requires 523.2145 amu, found 523.2121; HR-FAB-MS:
C33H29O5 requires 505.2032 amu, found 523.2015; EIþ-MS:
MIþ ¼ C33H30O6; m/z: 504.2 (90%) ¼ [MI ꢁ H2O]þ, 387.1
(100%) ¼ [MI – CH2(C6H4CO2H)]þ.
Standard Method for Saponification Reactions
The ester (1 equiv.) and LiOH (2 equiv. per ester) were dissolved
in 9:1 H2O/MeOH or H2O/EtOH depending upon the ester and
refluxed overnight. After cooling to room temperature the sol-
vent was removed under reduced pressure, the remaining solu-
tion diluted with H2O, cooled in an ice-bath and the pH adjusted
to 3 by the addition of HCl (1 M). The precipitate was collected
filtered and product dried under vacuum.
Preparation of Selected Compounds
1,3,5-Tris[(1E)-20-(ethyl 400-benzoate)vinyl]benzene (10)
1,2,4-Tris[(1E)-20-(ethyl 400-benzoate)vinyl]benzene (14)
Prepared as per the standard procedure using 1,3,5-tribromo-
benzene 8 (1010 mg, 3.21 mmol), Pd2(dba)3ꢂCHCl3 (882mg,
0.85 mmol), t-Bu3PHBF4 (560 mg, 1.93 mmol), Cy2NMe
(3.0 mL), ethyl 4-vinylbenzoate 7 (1870 mg, 10.61 mmol) and
THF (40 mL). The product was eluted with 2:98 MeOH/CH2Cl2
and recrystallized from CH2Cl2/EtOH to give 10 as an off white
powder (1.86 g, 97%).
1H NMR (600 MHz, CDCl3): d 1.42 (t, J 7.1, 9H, CH3), 4.40
(q, J 7.1, 6H, CH2), 7.24 (AB quartet, 6H, vinyl), 7.60 (d, J 8.3,
6H, ArH), 7.61 (s, 3H, ArH), 8.06 (d, J 8.3, 6H, ArH).
13C NMR (150 MHz, CDCl3): d 14.51 (CH3), 61.13 (CH2),
125.0 (CH), 126.5 (CH), 128.7 (CH), 129.7 (C), 130.2 (CH),
130.5 (CH), 137.9 (C), 141.5 (C), 166.5 (C¼O). IR (KBr):
n [cmꢁ1] 2979, 2929, 1713, 1604, 1279, 1178, 1105, 762, 698;
HR-EIþ-MS: C39H36O6 requires 600.2512 amu, found
600.2513; EIþ-MS: MI ¼ C39H36O6; m/z: 600.3 (100%) ¼
MIþ, 555.2 (7%) ¼ [MI ꢁ EtO]þ; UV-Vis (CH2Cl2): l [nm]
(log e [Mꢁ1 cmꢁ1]) 258 [4.49], 330 [4.28]; fluorescence
Using the standard Heck cross-coupling procedure, 1,2,4-
tribromobenzene 13 (1.018 g, 3.2 mmol), ethyl 4-vinylbenzoate
9 (1.843 g, 10.5 mmol), Pd2(dba)3ꢂCHCl3 (87.6 mg, 0.08 mmol),
[(t-Bu)3PH]BF4 (122.6 mg, 0.42 mmol), Cy2NMe (3 mL) in
THF (40 mL) were heated for 17 h. The crude mixture was
subjected to flash chromatography eluting with neat CH2Cl2.
The crude product was recrystallised from CH2Cl2/EtOH to give
(1.681 g, 88%) of a pale yellow solid. 1H NMR (600 MHz,
CDCl3): d 1.409, 1.413, 1.416 (3 ꢀ t, J 7.1, 9H, CH3), 4.392,
4.394, 4.400 (3 ꢀ q, J 7.1, 6H, CH2), 7.06–7.11 (m, 2H, vinyl
CH), 7.17–7.28 (m, 2H, vinyl CH), 7.51–7.67 (cm, 9H), 7.73 (m,
1H, core ArH), 8.04–8.09 (cm, 6H, ArH); 13C NMR (150 MHz,
CDCl3): d 14.5 (CH3), 61.1, 61.13, 61.1 (CH2), 125.8 (CH),
126.5 (CH), 126.5 (CH), 126.6 (CH), 126.4 (CH), 127.3 (CH),
128.3 (CH), 128.4 (CH), 128.7 (CH), 129.6 (C), 129.8 (C), 129.8
(C), 130.2 (CH), 130.2 (CH), 130.3 (CH), 130.5 (C), 130.7 (C),
131.3 (C), 135.6 (C), 136.4 (C), 136.9 (C), 141.62 (C¼O),

Synthesis of Fluorescent DNA Intercalator Precursors
321
141.66 (C¼O), 141.7 (C¼O); IR (KBr): n [cmꢁ1] 2981, 1713
(nC¼O), 1604, 1278, 1178, 1107; HR-EIþ-MS: C39H36O6
requires 600.2512 amu, found 600.2504; EIþ-MS: MI ¼
C39H36O6; m/z: 600.2 (100%) ¼ MIþ, 555.2 (13.3%) ¼ [MI ꢁ
EtO]þ, 437.1 (70.1%) ¼ [MI ꢁ 2 ꢀ OEt ꢁ EtO2CH]þ.
(69.2 mg, 0.07 mmol), [(t-Bu)3PH]BF4 (75.4 mg, 0.26 mmol),
Cy2NMe (0.8 mL) in THF (8 mL) were treated under the afore-
mentioned cross-coupling procedure. The product was purified
by flash chromatography with CH2Cl2/MeOH (100:0–99:1) an
the eluent. The crude material was recrystallized from CH2Cl2/
EtOH to give triester 18 (541.2 mg, 82%) as a bright yellow
solid. 1H NMR (600 MHz, CDCl3): d 1.41 (t, J 7.1, 12H, CH3),
4.40 (q, J 7.1, 8H, CH2), 7.13 (d, J 16, 4H, vinyl CH), 7.56 (d, J
16.1, 4H, vinyl CH), 7.60 (d, J 8.3, 8H, ArH), 7.83 (s, 2H, core
ArH), 8.06 (d, J 8.3, 4H, ArH); 13C NMR (150 MHz, CDCl3):
d 14.3 (CH3), 61.0 (CH2), 125.2 (ArCH, core), 126.5 (ArCH),
128.1 (CH, vinyl), 129.7 (Cq), 130.1 (ArCH), 131.0 (CH, vinyl),
135.6 (C), 141.4 (C), 166.3 (C¼O); IR (KBr): n [cmꢁ1] 2981,
1710, 1637, 1617, 1604, 1282, 1180, 1107; HR-EIþ-MS:
C50H46O8 required 774.3193 amu, found 774.3506 ; EIþ-MS:
MI ¼ C50H46O8; m/z: 774.4 (100%) ¼ MIþ, 729.1 (16%) ¼
[MI ꢁ OEt]þ, 611.1 (45%) ¼ [MI ꢁ CH2(C6H4CO2Et)]þ.
UV-Vis (Solv): l [nm] (log e [Mꢁ1 cmꢁ1]) 258 [4.62], 312
[4.73], 346 [4.82]; fluorescence (CH2Cl2): excitation [nm]
(emission [nm]) 258 [455, 518], 312 [362, 381, 452], 346
[381, 454]; (cyclohexane) 336 [442].
UV-Vis (Solv): l [nm] (e [Mꢁ1 cmꢁ1]) 258 [4.53], 338
[4.83], 362 [4.76, shoulder]; fluorescence (CH2Cl2): excitation
[nm] (emission [nm]) 258 [436 (shoulder), 450], 338 [436
(shoulder), 450]; (cyclohexane) 334 [416, 440].
1,2,4-Tris[(1E)-20-(400-benzoic acid)vinyl]benzene (6)
Triester 14 (250 mg, 0.42 mmol) and LiOHꢂH2O (70.2 mg,
1.67 mmol) in 9:1 EtOH/H2O were treated as described in the
general saponifiaction procedure giving the triacid 6 (186.6 mg,
1
86%) as a yellow/brown solid; H-NMR (600 MHz, CDCl3):
d 8.06–7.61 (m, 17H, ArH, CH), 7.66 (d, J 8.3, 1H, CH¼CH),
7.48 (s, 2HHHH, CH¼CH), 7.32 (m, 2H, ArH); 13C NMR
(150 MHz, CDCl3): d 167.6 (3 ꢀ C¼O), 141.76 (C), 141.71
(C), 141.6 (C), 137.0 (C), 136.3 (C), 135.4 (C), 131.2 (CH),
130.7 (CH), 130.5 (CH), 130.44 (C), 130.38 (C), 130.2 (CH),
130.16 (CH), 130.18 (CH), 128.4 (C), 128.3 (C), 127.9 (C), 127.4
(CH), 127.35 (CH), 127.15 (C), 126.9 (CH), 125.5 (C); IR (KBr):
n[cmꢁ1] 2929, 1684(nC¼O), 1603, 1419, 1315, 1287, 1178, 1125,
763; HR-EIþ-MS: C33H24O6 requires 516.1572amu, found
516.1571.
1,2,4,5-Tetrakis[(20-(ethyl 400-benzoate)ethyl)benzene (19)
Triester 18 (200.4 mg, 0.24 mmol) and Pd/C (10% w/w, ca
30 mg) in 1:1 EtOH/CH2Cl2 (40 mL) was treated as described.
The crude product was recrystallized from CH2Cl2 and EtOH to
give compound 19 (147.1 mg, 79%) as a white solid. 1H NMR
(600 MHz, CDCl3): d 1.38 (t, J 7.2, 12H), 2.82 (m, 16H), 4.36 (q,
J 7.2, 8H), 6.81 (s, 2H), 7.18 (d, J 8.0 Hz, 8H, ArH), 8.00 (d, J
8.0 Hz, 8H, ArH); 13C NMR (150 MHz, CDCl3): d 14.8, 34.0,
37.8, 61.0, 128.5, 128.6, 129.8, 130.6, 136.9, 147.2, 166.7;
IR (KBr): n [cmꢁ1] 2980, 2935, 1716, 1611, 1285, 1176,
1107, 1022; HR-EIþ-MS: C50H54O8 requires 782.3819 amu,
found 782.3809 EIþ-MS: MI ¼ C50H54O8; m/z: 782.1 (4%) ¼
MIþ, 736.1 (27%) ¼ [MI ꢁ HOEt]þ, 573 (100%).
1,2,4-Tris[20-(ethyl 400-benzoate)ethyl]benzene (15)
Triester 14 (306 mg, 0.51mmol) and Pd/C (10% w/w, ca
40 mg) in 1:1 EtOH/CH2Cl2 (20 mL) was treated as described.
The crude product was recrystallised from THF and hexane
1
to give ester 15 305 mg (98%). H-NMR (600 MHz, CDCl3):
d 1.376, 1.381, 1.393 (3 ꢀ t, 3 ꢀ CH3, 9H), 2.79–2.95 (m, 12H),
4.33–4.40 (m, 6H), 6.86 (s, 1H), 6.95 (d, J 7.8, 1H), 7.04 (d, J 7.8,
1H), 7.17 (AB d, J 8.0, 2H), 7.19 (AB d, J 8.0, 2H), 7.21 (AB d, J
8.1, 2H), 7.95 (cm, J 7.7, 6H); 13C NMR (150 MHz, CDCl3):
d 14.48, 14.50, 34.0, 34.4, 37.2, 37.7, 38.1, 61.0, 61.0, 126.6,
128.43, 128.54, 128.56, 128.7, 129.5, 129.7, 129.8, 129.9, 136.7,
139.0, 139.3, 147.2, 147. 2, 147.3, 166.7, 166.8, 166.8; IR (KBr):
n [cmꢁ1] 2981, 2942, 1713, 1610, 1283, 1177, 1123, 1108; HR-
EIþ-MS: C39H42O6 requires 606.2981 amu, found 606.2975.
EIþ-MS: MI ¼ C39H42O6; m/z: 606.2 (6%) ¼ MIþ, 560.14
(36%) ¼ [MI ꢁ HOEt]þ, 397 (100%).
1,2,4,5-Tetrakis[20-(400-benzoic acid)ethyl]benzene (20)
Triester 19 (101.4 mg, 0.13 mmol), LiOHꢂH2O (51 mg,
1.22 mmol) in 9:1 EtOH/H2O (25 mL) were treated as described
in the general saponification procedure, to give tetraacid 20
1
(87.3 mg, 97%) as a white solid; H NMR (500.1 MHz, d6-
DMSO): d 2.77 (s, 16H, CH2CH2), 6.86 (s, 2H, H2), 7.26 (AB, J
8.3, 8H, H20), 7.84 (AB, J 8.3, 8H, H30); 13C NMR (125.8 MHz,
d6-DMSO): d 33.1, 36.8, 128.5, 128.6, 129.4, 136.3, 147.0,
167.3; IR (KBr): n [cmꢁ1] 2945, 2863, 1688, 1610, 1422, 1315,
1288, 1178; HR-EIþ-MS: C42H38O8 requires 670.2567 amu,
found 670.2562; EIþ-MS: MI ¼ C42H38O8; m/z: 517.0 (100%) ¼
[MI ꢁ H2O ꢁ CH2(C6H4CO2H)]þ, 499.0 (12%) ¼ [MI ꢁ
2(H2O) ꢁ CH2(C6H4CO2H)]þ, 381.0 (19.5%) ¼ [MI ꢁ H2O ꢁ
2CH2(C6H4CO2H)]þ, 135.0 ¼ [CH2(C6H4CO2H)]þ.
1,2,4-Tris[20-(400-benzoic acid)ethyl]benzene (16)
Triester 15 (200 mg, 0.33 mmol) and LiOHꢂH2O (92.2 mg,
2.15 mmol) in 9:1EtOH/H2O (25 mL) wastreated as describedin
the general saponification procedure, giving triacid 16 (161 mg,
94%). 1H NMR (500.1 MHz, d6-DMSO): d 2.77–2.91 (m, 12H,
methylene), 6.960 (AB, J 8.5, 1H), 6.967 (s, 1H), 7.07 (AB, J 8.5,
1H), 7.271 (AB, J 8.4, 2H), 7.296 (AB, J 8.4, 2H), 7.299 (AB, J
8.4, 2H), 7.82–7.87 (m, 6H), 12.83 (br s, CO2H); 13C NMR
(125.8 MHz, d6-DMSO): d 33.1, 33.5, 36.3, 36.7, 37.0, 126.2,
128.5, 128.6, 128.6, 128.6, 129.0, 129.3, 129.4, 136.4, 138.6,
138.7, 146.9, 146.9, 167.3, 167.3; IR (KBr): n [cmꢁ1] 1688,
1610, 1422, 1315, 1289, 1178; HR-EIþ-MS: C33H30O6 requires
522.2042 amu, found 522.2045; EIþ-MS: MI ¼ C33H30O6;
m/z: 522.2 (9%) ¼ MIþ, 504.2 (86%) ¼ [MI ꢁ H2O]þ, 387.1
(100%) ¼ [MI – CH2(C6H4CO2H)]þ.
1,4-Bis[(1E)-20-(ethyl 400-benzoate)vinyl]benzene (28)
Method A: 1,4-Dibromobenzene 26 (101.5 mg, 0.43 mmol),
ethyl 4-vinyl benzoate 7 (166mg, 0.94mmol), Pd2(dba)3ꢂCHCl3
(45.1 mg, 0.04 mmol), [(t-Bu)3PH]BF4 (52.2 mg, 0.18 mmol),
Cy2NMe (300 mL) in THF (5 mL) were heated at reflux over-
night. The THF was removed under reduced pressure, the crude
product purified using flash chromatography with CH2Cl2 as
the eluent. Additional recrystallisation from CH2Cl2 and EtOH,
gave 28 (152.2 mg, 84%).
1,2,4,5-Tetrakis[(1E)-20-(ethyl 400-benzoate)vinyl]
benzene (18)
Method B: 1,4-dichlorobenzene 27 (59.9 mg, 0.41 mmol),
ethyl 4-vinyl benzoate 7 (160mg, 0.91mmol), Pd2(dba)3ꢂCHCl3
(42.1 mg, 0.04 mmol), [(t-Bu)3PH]BF4 (47.7 mg, 0.16 mmol),
1,2,4,5-Tetrabromobenzene 17 (255.8mg, 0.66mmol), ethyl-
4-vinylbenzoate 9 (498.6 mg, 2.83 mmol), Pd2(dba)3ꢂCHCl3

322
N. A. Lengkeek et al.
Cy2NMe (300 mL) in THF (5 mL) were heated at reflux for
3 days. The reaction mixture was concentated under reduced
pressure, the crude product was purified by chromatography
with CH2Cl2 as the eluent. Additional recrystallisation from
CH2Cl2 and EtOH, gave 28 49.8 mg (29%).
1H NMR (600MHz, CDCl3): d 1.41 (t, J 7.1, 6H), 4.39 (q, J
7.1, 4H), 7.14 (AB, J 16.3, 2H, vinyl CH), 7.24 (AB, J 16.3, 2H,
vinyl CH), 7.55 (s, 4H), 7.57 (d, J 8.1, 4H), 8.04 (d, J 8.1, 4H);
13C NMR (150MHz, CDCl3): d 14.5 (CH3), 61.1 (CH2), 126.5
(CH), 127.4 (CH), 128.0 (CH), 129.5 (C), 130.2 (CH), 130.7
Method 2: Diacid 3 (107.2 mg, 0.25 mmol) and Pd/C (10%
w/w ca 10 mg) in 1:1 EtOH/CH2Cl2 (10 mL) was treated as
described. The crude mixture containing 29 (103 mg, 96%) was
suspended in 9:1 EtOH/H2O (10 mL) and LiOHꢂH2O (26.3 mg,
0.63 mmol) added and treated under the general saponification
procedure described earlier to afford diacid 3 (73.2 mg, 82%).
1H NMR (500.1 MHz, d6-DMSO): d 2.88 (AA0BB0, 8H,
CH2CH2), 7.11 (s, 4H, H2/H3), 7.32 (d, J 8.2, 6H, ArH), 7.85
(d, J 8.2, 6H, ArH); 13C NMR (125.8 MHz, d6-DMSO): d 36.2,
37.0, 128.3, 128.6, 129.3, 138.7, 146.8, 167.3; IR (KBr):
n [cmꢁ1] 2944, 2923, 1685 (C¼O), 1610, 1425, 1318, 1292,
1180, 537.
(CH), 136.9 (C), 141.8 (C), 166.5 (C¼O); IR (KBr): n [cmꢁ1
]
2984, 2925, 1716 (C¼O), 1708 (C¼O), 1279, 1179, 1107; HR-
EIþ-MS: C28H26O4 requires 426.1831 amu, found 426.1824
UV-Vis (Solv): l [nm] (log e [Mꢁ1 cmꢁ1]) 254 [3.85], 372
[4.74]; fluorescence (CH2Cl2): excitation [nm] (emission [nm])
254 [414, 437], 372 [414, 437]; (cyclohexane) 328 [393, 413].
1,3-Bis[20-(methyl 400-benzoate)vinyl]benzene (4)
Isophthaldehyde 30 (460 mg, 3.43 mmol), 22 (4.4 g,
8.95 mmol), NaOMe (20 mL, 1.0 M) in MeOH (100 mL) were
treated under analogous conditions to those described for the
preparation of alkene 23. The white precipitate was filtered,
washed with MeOH, and dried to give 4 (0.85 g, 62%). The
1,4-Bis[20-(methyl 400-benzoate)vinyl]benzene (23)
(Methyl 4-carboxybenzyl)triphenylphosphonium bromide
(22) (4.43 g, 9.02 mmol) was dissolved in MeOH (100 mL)
and treated with NaOMe (45 mL 0.222 M in MeOH). The
ensuing yellow solution was treated with terephthalaldehyde
(512 mg, 3.82mmol) in one portion and the resultant mixture
was heated at reflux for 17 h. The resulting yellow precipitate
formed was collected and washed with MeOH to give 23 (1.27 g,
1
product was a 44:56 mixture of the E/E and E/Z products. H
NMR (600.1 MHz, CDCl3): d 3.82 (s, CH3, ct), 3.83 (s, CH3,
E/E), 3.85 (s, CH3, E/Z), 6.64 (AB, J 12.4, trans vinyl CH, E/E),
6.67 (AB, J 12.4, trans vinyl CH, E/E), 6.76 (AB, J 12.3, trans
vinyl CH, E/Z), 6.81 (AB, J 12.3, trans vinyl CH, E/Z), 7.05 (dd,
J1 7.6, J2 1.4, H4, ee), 7.08 (s, H2, ee), 7.10 (d, J 7.7, H4/H6,
E/Z), 7.13 (AB, J 16.5, cis vinyl CH, E/Z), 7.17 (t, J 7.6, H5,
E/E), 7.25 (AB, J 8.2, H20, E/Z), 7.27 (t, J 7.7, H5, E/Z), 7.33
(AB, J 16.5, cis vinyl CH, E/Z), 7.36 (AB, J 8.2, ArH, E/Z), 7.46
(s, H2, E/Z), 7.50 (d, J 7.7, H4/H6, E/Z), 7.66 (AB, J 8.3, ArH,
E/Z), 7.76 (AB, J 8.4, H30, E/E), 7.84 (AB, J 8.3, ArH, E/Z), 7.92
(AB, J 8.4, ArH, E/Z); 13C NMR (150.9 MHz, CDCl3): d 52.1
(CH3), 52.1 (CH3), 126.2 (CH), 126.6 (CH), 127.0 (CH), 127.6
(CH), 127.9 (CH), 128.1 (C), 128.2 (C), 128.3 (C), 128.3 (CH),
128.3 (CH), 128.7 (CH), 128.9 (CH), 128.9 (CH), 129.2 (CH),
129.3 (CH), 129.3 (CH), 129.5 (CH), 129.6 (CH), 130.9 (CH),
131.7 (CH), 131.8 (CH), 136.6 (C), 136.8 (C), 136.8 (C), 141.6
(C), 141.9 (C), 165.9 (C), 165.9 (C), 166.0 (C); IR (KBr): n
[cmꢁ1] 1720, 1606, 1435, 1280, 1179, 1109; HR-EIþ-MS:
C26H22O4 requires 398.1518 amu, found 398.1518.
1
84%). 40:60 mixture of the E/E and E/Z products. H NMR
(500.1 MHz, CDCl3): d 3.834 (s, CH3, EE), 3.837 (s, CH3, EZ),
3.85 (s, CH3, EZ), 6.691 (AB, J 12.3, vinyl CH, EE), 6.726 (AB, J
12.3, vinyl CH, EZ), 6.735 (AB, J 12.3, vinyl CH, EE), 6.774 (AB,
J 12.3, vinyl CH, EZ), 7.10 (s, core ArH, EE), 7.23 (AB, J 8.3,
ArH, EZ), 7.326 (AB, J 16.4, vinyl CH, EZ), 7.345 (AB, J 8.4,
ArH, EE), 7.389 (AB, J 16.4, vinyl CH, EZ), 7.393 (AB, J 8.4,
ArH, EZ), 7.54 (AB, J 8.3, ArH, EZ), 7.72 (AB, J 8.5, ArH, EZ),
7.84 (AB, J 8.4, ArH, EE), 7.87 (AB, J 8.4, ArH, EZ), 7.85 (AB, J
8.5, ArH, EZ); 13C NMR (125.8 MHz, CDCl3): d 52.1 (CH3), 52.1
(CH3), 126.6 (CH), 126.9 (CH), 127.6 (CH), 128.2 (C), 128.2 (C),
128.3 (C), 128.7 (CH), 128.8 (CH), 129.1 (CH), 129.2 (CH), 129.3
(CH), 129.4 (CH), 129.6 (CH), 130.7 (CH), 131.6 (CH), 135.6 (C),
136.0 (C), 136.1 (C), 141.8 (C), 141.8 (C), 142.0 (C); IR (KBr):
n[cmꢁ1] 3011, 2959, 1716, 1606, 1436, 1276, 1182, 1109; HR-EI-
MS: C26H22O4 requires 398.1518 amu, found 398.1515.
1,3-Bis[20-(methyl 400-benzoate)ethyl]benzene (31)
The E/Z isomeric mixture 4 (499.3mg, 1.25mmol) and Pd/C
(10% w/w, ca ,50mg) in MeOH/CH2Cl2 (40 mL, 1:1) was
treated as described previously. The crude product was recrys-
tallized from CH2Cl2/MeOH to give ester 31 (489.7mg, 98%)
as a white solid. 1H NMR (600MHz, CDCl3): d 2.8–2.96
(AA0BB0, 8H, CH2CH2), 3.90 (s, 6H, Me), 6.91 (s, 1H, H2),
6.99(dd, 2H, J 7.6 and1.4, 2H, H4/H6), 7.16–7.25 (cm, 5H, ArH),
7.96 (d, J 8.2, 4H, H30); 13C NMR (150MHz, CDCl3): d 37.5,
38.0, 52.1, 126.3, 128.0, 128.5, 128.7, 128.8, 129.8, 141.3, 147.3,
167.2; IR(KBr):n [cmꢁ1] 1715, 1607(m), 1438, 1279, 1109;HR-
EIþ-MS: C26H26O4 requires 402.1831 amu, found 402.1840.
1,4-Bis[20-(methyl 400-benzoate)ethyl]benzene (24)
Diester 23 (1.27 g, 3.19 mmol) and Pd/C (10% w/w ca
100 mg) in 1:1 MeOH/CH2Cl2 (30 mL) was treated as described
in the general procedure section. The crude product was recrys-
tallized from CH2Cl2 and MeOH to give (1.20 g, 93%) as a
white solid; 1H NMR (600 MHz, CDCl3): d 2.93 (AA0BB0, 8H,
CH2CH2), 3.91 (s, 6H, OCH3), 7.05 (s, 4H, H2/H3), 7.21 (d, J
7.6, 4H, H20), 7.95 (d, J 7.6, 4H, H30); 13C NMR (150 MHz,
CDCl3): d[ppm] 37.2, 38.0, 52.1, 128.1, 128.6, 128.7, 129.8, 139.0,
147.3, 167.3; IR (KBr): n [cmꢁ1] 2944, 2923, 1726, 1609, 1431,
1280, 1176, 1105. HR-EIþ-MS: C26H26O4 requires 402.1831 amu,
found 402.1834; EIþ-MS: MI ¼ C26H26O4; m/z: 402.2 (8%) ¼
MIþ, 370.1 (33.2%) ¼ [MI ꢁ MeOH]þ, 253.1 (100%) ¼ [MI ꢁ
CH2C6H4CO2Me]þ, 149.1 ¼ [CH2C6H4CO2Me]þ.
1,3-Bis[20-(400-benzoic acid)vinyl]benzene (32)
Ester 25 (202.6 mg, 0.50 mmol), LiOHꢂH2O (92.2 mg,
2.20 mmol) and 9:1 MeOH/H2O (30 mL) were treated as
described in the general saponfication procedure, giving
(175.8 mg, 94%) as a white solid. 1H NMR (500.1 MHz,
d6-DMSO): d 2.87 (AA0BB0, 8H, CH2CH2), 6.99–7.05 (m, 3H,
ArH), 7.15 (t, J 7.4, 1H, H5), 7.31 (AB, J 8.4, 4H, H20), 7.84 (AB,
J 8.4, 4H, H30), 12.8 (br s, 2H, CO2H); 13C NMR (125.8 MHz,
d6-DMSO): d 36.5, 37.0, 126.0, 128.1, 128.4, 128.6, 128.6,
1,4-Bis[20-(400-benzoic acid)ethyl]benzene (25)
Method 1: Diester 24 (308.6 mg, 0.77 mmol), LiOHꢂH2O
(125 mg, 3.0 mmol) in MeOH/H2O (9:1, 20 mL) were treated as
described in the general saponification procedure, to provide
diacid 25 280 mg (97%).

Synthesis of Fluorescent DNA Intercalator Precursors
323
129.3, 141.0, 146.9, 167.3; HR-EIþ-MS: C24H22O4 requires
374.1518 amu, found 374.1523; EIþ-MS: MI ¼ C24H22O4;
m/z: [%] ¼ MIþ, 239.0 (100%) ¼ [MI ꢁ CH2(C6H4CO2H)]þ,
193.0 (34%) ¼ [MI ꢁ CH2(C6H4CO2H) ꢁ CO2H ꢁ Hþ]þ.
Heck cross coupling reaction are more activated that the first. The
reaction could also be classified as a multiple Heck reaction as in the
previously reported cases. By Braese, Stefan; De Meijere, Armin,
Handbook of Organopalladium Chemistry for Organic Synthesis
2002, 1, 1179–1208 (John Wiley & Sons, Inc).
[16] T. Jeffery, Tetrahedron Lett. 1985, 26, 2667. doi:10.1016/S0040-4039
(00)98131-0
Acknowledgements
The authors would like to thank the National Health and Medical Research
Council. R.A.B. is the recipient of a UWA postgraduate award. Dr Ben
Corry, Dr Lindsay Byrne and Dr Anthony Reeder are gratefully acknowl-
edged for their assistance with fluorescence spectroscopy, NMR spectro-
metry and mass spectrometry respectively.
¨
[17] (a) W. A. Herrmann, C. B. Broßmer, K. Ofele, C.-P. Reisinger, T.
Priermeier, M. Beller, H. Fisher, Angew. Chem. Int. Ed. Engl. 1995,
34, 1844. doi:10.1002/ANIE.199518441
(b) L. F. Tietze, S. G. Stewart, M. E. Polomska, A. Modi, A. Zeeck,
Chemistry 2004, 10, 5233. doi:10.1002/CHEM.200400342
[18] M. Castella, F. Calahorra, D. Sainz, D. Velasco, Org. Lett. 2001, 3,
541. doi:10.1021/OL000370S
References
[19] E. D´ıez-Barra, J. C. Garc´ıa-Mart´ınez, S. Merino, R. del Rey,
J. Rodr´ıguez-Lo´pez, P. Sa´nchez-Verdu´, J. Tejeda, J. Org. Chem.
2001, 66, 5664. doi:10.1021/JO015764R
[1] (a) A. Rescifina, M. A. Chiacchio, A. Corsaro, E. De Clercq,
D. Iannazzo, A. Mastino, A. Piperno, G. Romeo, R. Romeo, V. Valveri,
J. Med. Chem. 2006, 49, 709. doi:10.1021/JM050772B
[20] J. Nierle, D. Kuck, Synlett 2006, 18, 2914.
(b) N. J. Wheate, C. R. Brodie, J. G. Collins, S. Kemp, J. R. Aldrich-
Wright, Mini Rev. Med. Chem. 2007, 7, 627. doi:10.2174/
138955707780859413
(c) Y. Pommier, Chem. Rev. 2009, 109, 2894. doi:10.1021/CR900097C
(d) E. White, Curr. Pharm. Des. 2006, 12, 3645. doi:10.2174/
138161206778522083
[21] A. Peruga, J. A. Matta, D. Sainz, E. Peris, J. Organomet. Chem. 2001,
637–639, 191. doi:10.1016/S0022-328X(01)00903-2
[22] (a) A. F. Littke, G. C. Fu, J. Am. Chem. Soc. 2001, 123, 6989.
doi:10.1021/JA010988C
(b) M. R. Netherton, G. C. Fu, Org. Lett. 2001, 3, 4295. doi:10.1021/
OL016971G
[2] (a) W. Shi, R. S. Coleman, T. L. Lowary, Org. Biomol. Chem. 2009, 7,
(c) S. G. Stewart, D. Spagnolo, M. E. Polomska, M. Sin, M. Karimi, L.
J. Abraham, Bioorg. Med. Chem. Lett. 2007, 17, 5819. doi:10.1016/J.
BMCL.2007.08.042
3709. doi:10.1039/B909153J
(b) A. K. Ray, U. Diederichsen, Eur. J. Org. Chem. 2009, 4801.
[3] I. Puskas, M. Schmitt, US patent 4,537,985.
[23] T. W. Campbell, R. N. McDonald, J. Org. Chem. 1959, 24, 1246.
doi:10.1021/JO01091A022
[24] A. Mylona, J. Nikokavouras, I. M. Takakis, J. Org. Chem. 1988, 53,
[4] J. Gross, G. Harder, A. Siepen, J. Harren, F. Vo¨gtle, H. Stephan,
K. Gloe, B. Ahlers, K. Cammann, K. Rissanen, Chemistry 1996, 2,
1585. doi:10.1002/CHEM.19960021218
[5] M. Uda, A. Momotake, T. Arai, Org. Biomol. Chem. 2003, 1, 1635.
doi:10.1039/B303412G
[6] S. Nakatsuji, K. Matsuda, Y. Uesugi, K. Makashima, S. Akiyama,
G. Katzer, W. Fabian, J. Chem. Soc., Perkin Trans. 2 1991, 861.
doi:10.1039/P29910000861
[7] Z. I. Niazimbetova, A. Menon, M. E. Galvin, D. Evans, J. Electroanal.
Chem. 2002, 529, 43. doi:10.1016/S0022-0728(02)00940-3
[8] A. Sharma, N. Sharma, R. Kumar, A. Shard, A. K. Sinha, Chem.
Commun. 2010, 46, 3283. doi:10.1039/C001980A
3838. doi:10.1021/JO00251A032
[25] T. Schrievers, U. H. Brinker, Synthesis 1988, 330. doi:10.1055/
S-1988-27561
[26] (a) R. N. Beale, E. M. F. Roe, J. Chem. Soc. 1952, 2755.
(b) J. C. Roberts, J. A. Pincock, J. Org. Chem. 2006, 71, 1480.
doi:10.1021/JO052123D
(c) Y. V. Il’ichev, W. Ku¨hnle, K. A. Zachariasse, Chem. Phys. 1996,
211, 441. doi:10.1016/0301-0104(96)00200-5
[27] R. Benshafrut, M. Rabinovitz, Z. Dee-Noor-Barzily, A. J. de Meijere,
Phys. Org. Chem 1999, 12, 333. doi:10.1002/(SICI)1099-1395
(199904)12:4o333::AID-POC11843.0.CO;2-J
[9] I. P. Beletskaya, A. V. Cherpakov, Chem. Rev. 2000, 100, 3009.
doi:10.1021/CR9903048
[28] (a) H. Meier, R. Zertani, K. Noller, D. Oelkrug, G. Krabichler, Chem.
Ber. 1986, 119, 1716. doi:10.1002/CBER.19861190523
(b) A. E. Siegrist, P. Liechti, H. R. Meyer, K. Weber, Helv. Chim. Acta
1969, 52, 2521. doi:10.1002/HLCA.19690520836
(c) J. L. Segura, R. Gmez, N. Martn, D. M. Guldi, Org. Lett. 2001, 3,
2645. doi:10.1021/OL016083L
[10] W. Tao, S. Nesbitt, R. F. Heck, J. Org. Chem. 1990, 55, 63.
doi:10.1021/JO00288A013
[11] (a) D. A. Alonso, C. Na´jera, C. M. Pacheco, Adv. Synth. Catal.
2002, 344, 172. doi:10.1002/1615-4169(200202)344:2o172::AID-
ADSC17243.0.CO;2-9
(b) S. D. Bull, S. G. Davies, A. D. Smith, J. Chem. Soc., Perkin
Trans. 1 2001, 2931. doi:10.1039/B107440G
(c) F. Berthiol, I. Kondolff, H. Doucet, M. Santelli, J. Organomet.
Chem. 2004, 689, 2786. doi:10.1016/J.JORGANCHEM.2004.06.007
[12] (a) A. Lansky, O. Reiser, A. De Meijere, Synlett 1990, 405.
doi:10.1055/S-1990-21107
[29] (a) D. H. Waldeck, Chem. Rev. 1991, 91, 415. doi:10.1021/
CR00003A007
(b) E. Gilabert, R. Lapouyade, C. Rullie`re, Chem. Phys. Lett. 1988,
145, 262. doi:10.1016/0009-2614(88)80004-6
[30] A. A. Kubicki, Chem. Phys. Lett. 2003, 373, 471.
[31] M. Frigerio, M. Santagostino, S. Sputore, J. Org. Chem. 1999, 64,
4537. doi:10.1021/JO9824596
[32] J. Gross, G. Harder, A. Siepen, J. Harren, F. Vo¨gtle, H. Stephan,
K. Gloe, B. Ahlers, K. Cammann, K. Rissanen, Chemistry 1996, 2,
1585. doi:10.1002/CHEM.19960021218
[33] T. Ukai, H. Kawazazura, Y. Ishui, J. J. Bonnet, J. A. Ibers,
J. Organomet. Chem. 1974, 65, 253. doi:10.1016/S0022-328X(00)
91277-4
[34] D. R. Coulson, Inorg. Synth. 1972, 13, 121. doi:10.1002/
9780470132449.CH23
[35] K. B. Sharpless, R. Oi, Org. Synth. 1996, 73, 1.
[36] (a) R. Broos, D. Tavernier, M. J. Antunis, Chem. Ed. 1978, 55, 813.
doi:10.1021/ED055P813
(b) B. Stulgies, P. Prinz, J. Magull, K. Rauch, K. Meindl, S. Ru¨hl, A.
de Meijere, Chemistry 2005, 11, 308. doi:10.1002/CHEM.200400723
[13] J. N. G. Pillow, P. L. Burn, I. D. W. Samual, M. Halim, Synth. Met.
1999, 102, 1468. doi:10.1016/S0379-6779(98)00541-4
[14] A. J. Amoroso, J. P. Maher, J. A. McCleverty, M. D. Ward, J. Chem.
Soc. Chem. Commun. 1994, 1273. doi:10.1039/C39940001273
[15] In the reported transformation the individual Heck cross coupling
reactions are assumed to either occur simultaneously or one after each
other. This reaction cannot be classified as a domino reaction defined
as ‘a transformation of two or more bond forming reactions under
identical reaction conditions, in which the latter transformations take
place at the functionalities obtained in the former bond forming
reactions.’ L. F. Tietze, G. Brasche, K. M. Gericke, Domino Reactions
in Organic Synthesis 2006 (Wiley-VCH Verlag GmbH & Co. KGaA:
Weinheim). The transformation in this case could be classified as a
tandem reaction because the reaction sites are different from one
another and it could be assumed that the products following the first
(b) D. L. Tullen, B. A. J. Hess, J. Chem. Ed. 1971, 48, 476.
doi:10.1021/ED048P476
(c) J. H. Ackerman, A. R. Surrey, Org. Synth. 1967, 47, 76.