Switching between ring closed and open N-incorporated heterocycles with tuneable charges and modular reactivity based upon 5-(2-bromoethyl) phenanthridinium bromide

Article abstract of DOI:10.1039/c2ob06708k

5-(2-bromoethyl)phenanthridinium bromide (BEP) undergoes a 3-step-one-pot cyclisation reaction with primary amines allowing the facile synthesis of a vast library of heterocycles. A diverse range of primary aryl amines were explored as reactants to gain insight into the product isolated as a result of the steric and electronic effects of the aryl precursors. Analysis and reaction monitoring with UV-vis and NMR spectroscopy revealed that excessively electron withdrawing groups and sterically hindered amines do not allow for isolation of the common neutral tetrahydroimidazophenanthridine (TIP) structure but allow either the isolation of the charged dihydroimadazophenanthridinium (DIP) or aminoethylphenanthridinium (AEP) products.

Full text of DOI:10.1039/c2ob06708k

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PAPER
Switching between ring closed and open N-incorporated heterocycles with
tuneable charges and modular reactivity based upon 5-(2-bromoethyl)
phenanthridinium bromide†
Roslyn Eadie, Craig Richmond, Samantha Moreton and Leroy Cronin*
Received 9th October 2011, Accepted 20th December 2011
DOI: 10.1039/c2ob06708k
5-(2-bromoethyl)phenanthridinium bromide (BEP) undergoes a 3-step-one-pot cyclisation reaction with
primary amines allowing the facile synthesis of a vast library of heterocycles. A diverse range of primary
aryl amines were explored as reactants to gain insight into the product isolated as a result of the steric and
electronic effects of the aryl precursors. Analysis and reaction monitoring with UV-vis and NMR
spectroscopy revealed that excessively electron withdrawing groups and sterically hindered amines do not
allow for isolation of the common neutral tetrahydroimidazophenanthridine (TIP) structure but allow
either the isolation of the charged dihydroimadazophenanthridinium (DIP) or
aminoethylphenanthridinium (AEP) products.
also makes intercalation between bases pairs a potential inter-
Introduction
action.9 In addition, the dihydroimidazolium ring helps prevent
reduction8 and provides resistance to pseudo base formation, a
Heterocyclic organic molecules are vital components of all bio-
logical systems, for example, DNA base units, amino acids and
vitamins, as well as naturally occurring drugs such as morphine
and quinine.1 Their susceptibility to structural modifications
allows the discovery of new systems which could lead to further
applications in the pharmaceutical industry2–4 as herbicides, pes-
ticides,5 and drugs, making them excellent candidates for further
study. As such many studies have focused on nitrogen containing
heterocycles as they generally have a high affinity for DNA,4,6,7
and therefore form a strong platform from which to create new
anticancer therapeutics, and a tool box to explore small-molecule
nucleic acid interactions.
A short time ago a new family of nitrogen containing hetero-
cycles based on a phenanthridinium framework was discovered
by Cronin and Parenty. This 3-step-one-pot cyclisation reaction
was found to be general between the phenanthridinium frame-
work and a large range of primary amines yielding charged
planar aromatic dihydroimidazophenanthridinium cations
(DIPs).8 Due to the features of the DIP structures, it was orig-
inally thought that they would be suitable DNA targeting agents;
their cationic nature allows for attraction to anionic substances
such as the phosphate backbone and the flat aromatic framework
common drawback of phenanthridinium-based anticancer
agents.10 Avoiding these structural changes is important for
retention of activity as they disrupt the planarity and remove the
positive charge, the features necessary for their biological func-
tion.11 Based on these rationales, studies were conducted on a
range of DIP derivatives, where it was found that they showed
promise as candidates for application in cancer therapy because
of their DNA binding abilities and potent and unusual activity in
a range of cancer cell lines.8,12,13 However, a major drawback
with the cationic DIP framework was their low therapeutic
indices and toxic side-effects thought to be caused by non-
specific DNA binding or by other mechanisms such as mem-
brane insertion.12,14
The 3-step-one-pot cyclisation reaction, reported by Cronin
and Parenty, involves nucleophilic attack by a primary amine at
the α-position of 5-(2-bromoethyl)phenanthridinium bromide
(BEP) followed by a 5-exo-tet cyclisation and a final oxidation
step to give the DIP product. The cyclised intermediate formed
prior to oxidation is the tetrahydroimidazophenanthridine (TIP)
structure, for which a method of isolation has only recently been
reported.15 Isolation of the TIPs not only provided mechanistic
information on this new reaction sequence but also allowed for
the formation of another new family of compounds, the ami-
noethylphenanthridiniums (AEPs)16 (Scheme 1). These AEPs
form via protonation and ring opening of the cyclic TIP
intermediates.
WestCHEM, School of Chemistry, University of Glasgow, Glasgow,
United Kingdom, G12 8QQ. E-mail: Lee.Cronin@glasgow.ac.uk; Tel: +
44 141 330 6650
†Electronic supplementary information (ESI) available: 1H NMR
spectra of isolated compounds and UV-vis spectra for kinetic exper-
iments. See DOI: 10.1039/c2ob06708k
Contrary to the DIP, the TIP structure is neutral and non-
planar and could therefore reduce the toxic side-effects
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Table 1 Selected aryl amines and their product percentage yields using
the standard conditions for synthesis
Amine
TIP(% yield)
DIP(% yield)
6-benzo-thiazolamine
2-benzo-thiazolamine − (0)
− (0)
6-amino-
benzimidazole
2-amino-
− (0)
− (0)
benzimidazole
2-methyl-4-(3-
aminophenyl)
thiazole
Scheme 1 Synthetic outline for the preparation of the TIP, DIP and
AEP heterocycles (i) NH2R (1 eq.) and triethylamine (3 eq.) in
chloroform.
2-amino-4-(p-tolyl)
– (0)
– (0)
thiazole
oxidation was also established. Both of these features are impor-
tant because the AEP can act as a hydride acceptor, irreversibly
consuming the TIP to generate the DIP and 5-(2-aminoethyl)-
5,6-dihydrophenanthridine (AEDP). The inherent co-existence of
the TIP reductant and AEP oxidant is the reason only TIP deriva-
tives produced mainly from substituted aryl amines have been
successfully isolated.15
Herein we report the study of the reaction pathways observed
as a result of the amine substituent when reacted with the BEP
starting material. Three topics were studied to gain further
insight into this influence: Electronic effects from aryl substitu-
ents, steric effects from ortho substituents, and effects of neigh-
bouring hydroxyls and ring-based nitrogen atoms, the latter
being a finer extension of the former two.
Scheme 2 Relationship between the TIP, DIP AEP and AEDP struc-
tures by way of pH control.
previously observed for the DIPs.17 Similar neutral non-planar
heterocycles have also been shown to have applications in anti-
bacterials, fungicides and other biological actions.18–20 Despite
this, the TIP structures have been much less studied due to their
reduced stability in comparison to the DIP structures. This lower
stability comes from their susceptibility towards oxidative and
acidic conditions, making isolation more difficult. For these
reasons successful TIP isolation has been to a greater extent
more challenging and until now attempts to expand the library of
TIP compounds have not yet had the same level of success as
was experienced with the DIPs. During the expansion of the TIP
library it was observed that isolation relied upon the substituent
of the amine chosen for the reaction being sufficiently electron
withdrawing. This was because in order to reduce the possibility
of ‘hydride loss’ (oxidation) the availability of the nitrogen lone
pair had to be moderated. Equally it could not be excessively
electron withdrawing as this consequently caused the nucleophi-
lic nitrogen to be too weak to attack the α-position of the BEP;
finding the exact balance point was therefore crucial for control-
ling the outcome of these reactions.15
Results and discussion
Electronic effects
The first group of amines considered comprised a set of amine
reactants where the amine itself was directly conjugated to two
other highly electronegative elements (nitrogen and sulphur) and
their isomers in which the amine is at the other end of the mol-
ecule and not directly conjugated to them (Table 1 and
Scheme 3). When the nucleophilic nitrogen was conjugated to
the benzene ring, and not directly to the other electronegative
elements in the amine structure, it was possible to isolate the cor-
responding TIP structures using the normal TIP reaction method
(Scheme 3). This method involves adding the amine (1 eq.)
along with base, triethylamine (3 eq.), to a suspension of BEP (1
eq.) in chloroform and stirring at room temperature until a sol-
ution forms.
The reversible relationship between the TIP and AEP struc-
tures is another aspect that was discovered and the equilibrium
between these two structures can be related to the pKa of the
primary amine reactants. Aliphatic amines tend to have a higher
pKa than aryl amines, thus increasing the degree of protonation
at lower pH and hence production of the corresponding AEP via
ring opening (Scheme 2). A relationship between pKa and TIP
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Table 2 Selected aryl amines with varying ortho-position bulk and the
isolated product from reactions using the general chloroform method for
TIP synthesis
Amine
Product isolated
% Yield
32
5-amino-1,10-phenanthroline
2-aminofluorene
90
53
3-aminofluoranthene
Scheme 3 Comparison of reaction path and reaction outcome between
the amine isomers, 2-methyl-4-(3-aminophenyl)thiazole and 2-amino-4-
(p-tolyl)thiazole.
2-ethynylaniline
82
The use of chloroform as a solvent acts as a visual aid to the
end point of the reaction; BEP is sparingly soluble in chloroform
and the TIP products are soluble thus providing an indicator as
to when the reaction is complete by conversion from a suspen-
sion to a solution.15 A water and brine wash followed by solvent
concentration under vacuum yields the crude TIP product, which
can be further purified through methanol triturations. However,
when the amine responsible for the nucleophilic attack on the
α-position of the BEP was in direct conjugation with the electro-
negative substituents, no TIP was isolated from the reactions
under these conditions. 1H NMR studies carried out in both
chloroform and methanol revealed phenanthridinium pseudo
base formation17 only (see ESI†).
By comparison of 2-methyl-4-(3-aminophenyl)thiazole and its
isomer 2-amino-4-(p-tolyl)thiazole, it can be seen that simply
rearranging the amine structure prevents the TIP from success-
fully forming. The existence of the tautomeric forms21–23 is
thought to be a contributing factor for those reactions yielding
no product. Although the amine form is the predominant tauto-
mer,24 the presence of the tautomeric equilibrium results in
lower nucleophilicity of the amine.3,25,26
the substituent was simply a proton, the reaction was permitted
to proceed as normal and the chloroform reaction method
yielded the TIP (8) as expected, typically in high yields as can
be seen with the reaction using 2-aminofluorene.
However when the substituent at the ortho-position increased
in size, the TIP was not able to be isolated and in these cases the
DIP or singly charged AEP was obtained: With 2-ethynylaniline,
the reaction yielded the DIP (10), however when the steric bulk
at the ortho-position was increased further still, as in the cases of
both 3-aminofluoranthrene and 5-amino-1,10-phenanthroline, the
singly charged AEPs (7 and 9) were produced.
Structural analysis of the TIP has indicated that the amine side
chain and TIP hydride lie preferentially in a syn confor-
mation.15,17 While bulkier amino substituents have been reported
to help stabilise the TIP structure by creating a steric shield for
the “hydride” and therefore minimising its transfer, it has been
demonstrated here that when the sterics surrounding the nucleo-
philic nitrogen become too large, this is not the case and for-
mation of the DIP or AEP will be favoured. This is demonstrated
here where the slightly bulkier 2-ethynylaniline gave a solution
as expected when reacted using the conventional TIP method in
chloroform. Upon work-up, the crude product displayed some
This implies that the position of the amine in respect to elec-
tron withdrawing groups is crucial, and in the unsuccessful
attempts to synthesise the TIP, the amine side chain proved to be
excessively electron withdrawing, consequently causing the
nucleophilic nitrogen to be too weak to attack the α-position of
the BEP. Without a nitrogen possessing enough nucleophilicity,
the reactive BEP forms a pseudo base structure which can
further react/decompose to other undesired byproducts.
1
indication of the TIP structure along with the DIP form by H
NMR analysis however it was not possible to isolate the TIP
itself. It was thought that the TIP persists long enough to be seen
1
by H NMR but that the mild strain between the side chain and
TIP hydride results in rotation of the amine, ‘breaking’ the steric
shield and allowing oxidation to the DIP structure (10). On the
other hand, both 3-aminofluoranthene and 5-amino-1,10-phenan-
throline never developed a solution when reacted with the BEP
under the standard reaction conditions and analysis of the sus-
pensions showed no signs of the TIP, only clean singly charged
AEPs (7 and 9). Here the initial formation of the intermediate
must generate too much strain and the newly formed ring struc-
ture reopens almost immediately.
Substitution at the ortho-position of the amine
The second group of amines chosen (Table 2) show the
influence of substituents at the position ortho to the amine. 2-
ethynylaniline, 3-aminofluoranthene and 5-amino-1,10-phenan-
throline were chosen as they displayed a gradual increase in
steric bulk at the ortho-position when compared to 2-aminofluor-
ene whilst the electronic differences remained close enough to
retain the required nucleophilicity of the primary amine. When
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Table 3 Chosen aryl amines and isolated product from reactions using
the general method for TIP synthesis
Amine
Product isolated
% Yield
45
2-amino-5-chloropyridine
5-amino-2-chloropyridine
2-aminopyridine
15
29
49
Fig. 1 Spectra for the products, reactants and reaction mixture for the
reaction between 0.1 mM BEP solution (2 mL, 1 eq) and 0.1 mM 3-ami-
nofluoranthene and triethylamine solution (2 mL, 1 and 3 eq. respect-
ively) (i) 0.1 mM BEP, blue curve; (ii) 0.1 mM 3-aminofluoranthene, red
curve; (iii) product solution after 10 h, purple curve; (iv) 0.05 mM
pseudo base, green curve. (Inset) Plot of absorbance changes at 373 nm
against time.
2-aminophenol
4-hydroxy-3-aminopyridine
56
2-amino-3-hydroxypyridine
3-amino-2-hydroxypyridine
43
65
Taking into account that some of the experiments showed no
indication of the TIP forming when monitored only by 1H
NMR, timed UV experiments were carried out to support the
proposed mechanism of formation (Fig. 1). Solutions of amine
with triethylamine in acetonitrile were mixed and added to BEP
to closely mimic the normal reaction conditions; BEP (1 eq.)
with amine (1 eq.) and triethylamine (3 eq.). The BEP solution
was monitored for an hour and then the basic amine solution
was added and the reaction mixture was then monitored for a
further 9 h. At 373 nm, the 0.1 mM BEP solution absorbs rela-
tively strongly. On addition of the 3-aminofluoranthene (1 eq.)
and triethylamine (3 eq.), the intermediates (pseudo base, alpha-
adduct and TIP) are rapidly formed, none of which have an
absorbance at 373 nm. The amine itself absorbs weakly at
373 nm, which accounts for the observation that the absorbance
does not drop completely to zero upon addition. As the product
forms, the ring opens re-establishing the phenanthridinium ring
system and the absorbance increases.
For the reaction of the BEP and 2-aminofluorene (see ESI for
the UV-vis spectra†), the amine has no absorption at 373 nm, so
when the intermediates form upon addition of the 2-aminofluor-
ene and triethylamine, the absorbance drops to zero. However, as
the phenanthridinium ring system is not restored only a slight
absorbance rise at 373 nm is observed upon conversion to the
TIP. The monitored reaction for the DIP formation from BEP
and 2-ethynylaniline shows the same initial drop in absorbance
at 373 nm (see ESI for the UV-vis spectra†), however not to zero
as expected: Initially the absorbance can be attributed to residual
BEP, which is then converted to the product mixture. Unfortu-
nately, the absorbances for the reactants and products at 373 nm
for this particular reaction are very similar and therefore no
change in intensity at this wavelength is observed as the reaction
progresses.
nucleophilic nitrogen become too large, this is not the case and
formation of the DIP or AEP will be favoured. This is due to the
reduced stability of these TIPs favouring further reaction by
either oxidation or ring opening: The non-planarity of the TIP
structures creates an environment where interaction of the ortho
substituents with the TIP alpha proton are possible and increased
steric bulk at the ortho-position therefore leads to greater strain
which can be released via oxidation to the planar DIP or ring
opening to the AEP.
Effects of neighbouring hydroxyl groups and pyridine nitrogens
Finally, the effects brought about by including a hydroxyl group
and/or a pyridyl nitrogen were probed (Table 3). By incorporat-
ing a pyridyl ring or an ortho-hydroxyl group in the amine sub-
strate, the TIP was not isolated. With 2-amino-5-chloropyridine,
5-amino-2-chloropyridine and 2-aminopyridine, the reactions all
developed solutions after stirring at room temperature and after
the standard work up of the reaction all showed signs of the TIP
1
as anticipated when analysed by H NMR. However none of the
TIPs were able to be successfully isolated; instriethylamined, the
corresponding DIPs were yielded (11–13). When a hydroxyl
group was introduced into the amines used, the reactions never
formed solutions, even after 72 h.
While reactions monitored by H NMR showed initial traces
of TIP in the case of 2-aminophenol and 4-hydroxy-3-amino-
While bulkier amino substituents have been reported to help
stabilise the TIP structure by creating a steric shield for the
“hydride” and therefore minimising its transfer,15,17 it has been
demonstrated here that when the sterics surrounding the
1
pyridine, both of which ultimately yielded DIP structures (14
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1
and 15), H NMR studies of 2-amino-3-hydroxypyridine and 3-
hertz. The multiplicities are expressed as follows: s = singlet, d =
doublet, t = triplet, q = quartet, m = multiplet, brd = broad. All
spectra were recorded on Shimadzu FTIR 8400S Fourier Trans-
former Infrared Spectrophotometer; peaks are quoted in wave-
numbers (cm−1) and their relative intensities are reported as
follows: s = strong, m = medium, w = weak. UV-vis spec-
troscopy was performed on a JASCO V-670 Spectrophotometer.
Mass spectra were obtained on a JEOL JMS 700 spectrometer
operating in fast atom bombardment (FAB), electron ionization
(EI), or chemical ionization (CI) mode.
amino-2-hydroxypyridine revealed no traces of TIP, only the
singly charged AEPs (16 and 17), which were later isolated.
Even though none of the reactions yielded the TIP form and
some showed no traces of any TIP formation, all the reactions
carried out must have given the intermediate initially, due to the
reaction pathway followed (Scheme 1). However in all the cases
demonstrated, the TIP is not stable enough under the reaction
conditions and is either oxidised to the DIP or the imidazole ring
reopens to give the AEP. In the situation where the AEP was iso-
1
lated, H NMR studies showed no TIP at all, indicating that the
TIP form was particularly unstable and ring opening was very
fast.
1-Benzothiazol-6-yl-1,2,3,12b-tetrahydroimidazo[1,2-f]
phenanthridine (1)
The ortho-positioning of the hydroxyl alone cannot be attribu-
ted to the ring opening of TIPs to AEPs 16 and 17 as DIPs 14
and 15 are also synthesised from an amine with a hydroxyl ortho
to the nucleophilic amine. Rules regarding the reaction outcome
as a function of the relative position of the pyridyl nitrogen
cannot be established either and so predicting which route the
TIP takes, oxidation or ring opening, to release the strain of the
ring system and thus predicting whether the DIP or AEP will be
favoured is not possible from the current set of results. However
one thing that can be said is that both functionalities appear to
have a destabilising effect, making isolation of the corresponding
TIP structures unlikely.
To a suspension of BEP (700 mg, 1 eq) in chloroform (40 mL)
was added 6-aminobenzothiazole (286 mg, 1 eq) and triethyl-
amine (797 μL, 3 eq) and stirred at room temperature for 3.5 h.
The orange solution was washed with water, then brine and con-
centrated under vacuum. The orange honeycomb-like residue
was sonicated in methanol then filtered, yielding a pale cream
1
powder (540 mg, 80%). H NMR (CDCl3, 400 MHz): δ 8.76 (s,
1H), δ 8.03 (d, 1H, J = 8.8 Hz), δ 7.90 (d, 1H, J = 6.4 Hz), δ
7.81 (d, 1H, J = 7.2 Hz), δ 7.44 (t, 1H, J = 7.6 Hz), δ 7.36 (t,
1H, J = 8 Hz), δ 7.27 (t, 1H, J = 6.4 Hz), δ 7.19 (m, 2H), δ 7.07
(t, 1H, J = 7.2 Hz), δ 7.03 (dd, 1H), δ 6.86 (d, 1H, J = 8 Hz), δ
5.42 (s, 1H), δ 4.19 (m, 1H), δ 3.97 (t, 1H, J = 7.6 Hz), δ 3.72
(t, 1H, J = 7 Hz), δ 3.45 (m, 1H); 13C NMR (DMSO,
100 MHz): δ 151.6 (CH), δ 146.9 (C), δ 145.9 (C), δ 143.1 (C),
δ 135.2 (C), δ 133.5 (C), δ 131.6 (C), δ 129.3 (CH), δ 127.8
(CH), δ 127.0 (CH), δ 123.7 (CH), δ 123.6 (CH), δ 123.4 (CH),
δ 123.3 (C), δ 122.9 (CH), δ 119.7 (CH), δ 114.8 (CH), δ 113.2
(CH), δ 105.3 (CH), δ 74.6 (CH), δ 51.4 (CH2), δ 44.4 (CH2);
IR (KBr, cm−1): 3060 (w), 2840 (w), 1595 (m), 1444 (m), 1329
(m), 1198 (m), 817 (s), 746 (s); MS (FAB) for (C22H18N3S) (M
+ H)+ 356 (100), 193 (100), 180 (40), 154 (28), 136 (28);
HRMS (FAB) for (C22H18N3S) calculated 356.1221, found
356.1223.
Conclusions
In summary, we have presented evidence to support the 3-step
reaction mechanism for the reactions of primary amines with
BEP, in particular focusing on the influence the amine structure
and conformation has on the products isolated: Amines directly
conjugated to significantly electron withdrawing groups have
been shown to prevent formation of any of the desired structures
(TIP, DIP or AEP), whereas when the restricting group is distant
from the primary amine, all can be produced. When the aryl
amine has greater steric bulk at the ortho-position or N-contain-
ing aromatic rings such as pyridines, DIP or AEP formation is
favoured over that of TIP. This is due to the reduced stability of
these TIPs favouring further reaction by either oxidation or ring
opening. This heightened knowledge of the influence of the
amines environment on this reaction sequence is important since
it will allow the rational design of new TIP, DIP and AEP hetero-
cycles. This level of control will aid our future studies in the syn-
thesis and discovery of similar heterocyclic structures formed
from more complex and bio-relevant amines, with possible
applications in the pharmaceutical industry.
1-Benzothiazol-6-yl-2,3-dihydro-1H-imidazo[1,2-f]
phenanthridin-4-ylium bromide (2)
To a suspension of BEP (367 mg, 1 eq) in chloroform (25 mL)
was added 6-aminobenzothiazole (150 mg, 1 eq) and triethyl-
amine (416 μL), 3 eq) and stirred under nitrogen at room temp-
erature. The resulting solution was washed with water then brine,
and then concentrated to remove traces of triethylamine. The
residue was dissolved in ethyl acetate and NBS (178 mg, 1 eq)
added forming a creamy suspension which was filtered and col-
1
Experimental
lected as a peach powder (346 mg, 80%). H NMR (DMSO,
400 MHz): δ 9.63 (s, 1H), δ 8.93 (d, 1H, J = 8.4 Hz), δ 8.85 (d,
1H, J = 7.6 Hz), δ 8.62 (d, 1H, J = 2 Hz), δ 8.38 (d, 1H, J = 9.2
Hz), δ 8.05 (t, 1H, J = 7.2 Hz), δ 7.95 (t, 1H, J = 7.2 Hz), δ 7.88
(d, 1H, J = 8.0 Hz), δ 7.87 (d, 1H, J = 8.0 Hz), δ 7.74 (t, 1H, J =
7.6 Hz), δ 7.52 (t, 1H, J = 7.8 Hz), δ 7.31 (d, 1H, J = 8 Hz), δ
5.00 (t, 2H, J = 10.8 Hz), δ 4.68 (m, 2H); 13C NMR (DMSO,
100 MHz): δ 159.2 (CH), δ 153.4 (C), δ 152.8 (C), δ 136.4 (C),
δ 135.4 (CH), δ 135.3 (C), δ 135.1 (C), δ 132.6 (C), δ 131.6
(CH), δ 128.8 (CH), δ 127.2 (CH), δ 125.9 (CH), δ 125.0 (CH),
Instruments and materials
All starting materials and solvents were commercially available
(reagent grade) and were used as supplied, from Sigma-Aldrich
and Alfa Aesar Chemical Companies, without further purifi-
1
cation. H and 13C NMR were recorded on a Bruker DPX 400
spectrometer operating at 400 and 100 MHz, respectively.
Chemical shifts (δ) are given in parts per million (ppm) relative
to the residual solvent peak. Coupling constants (J) are given in
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δ 124.9 (CH), δ 124.32 (CH), δ 124.12 (CH), δ 121.20 (CH), δ
120.50 (C), δ 116.3 (CH), δ 115.2 (C), δ 54.7 (CH2), δ 47.0
(CH2); IR (KBr, cm−1): 3048 (w), 3028 (w), 1595 (m), 1579 (s),
1304 (m), 1238 (w), 940 (w), 846 (m); MS (FAB) for
(C22H16N3S) (M+) 354 (100), 179 (20), 160 (42), 101 (28), 80
(65), 46 (82), 16 (57); HRMS (FAB) for (C22H16N3S) (M+) cal-
culated 354.1065, found 354.1063.
(FAB) for (C22H17N4) (M+) calculated 337.1453, found
337.1450.
1-[3-(2-Methyl-thiazol-4-yl)-phenyl]-1,2,3,12b-
tetrahydroimidazo[1,2-f]phenanthridine (5)
To a suspension of BEP (500 mg, 1 eq) in chloroform (50 mL)
was added 4-(3-Aminophenyl)-2-methylthiazole (259 mg, 1 eq)
and Et3N (569 μL, 3 eq) and stirred at room temperature until a
solution formed. The reaction mixture was transferred to a separ-
ating funnel and washed with water, brine, dried over MgSO4
and concentrated under vacuum, giving a light brown honey-
comb like residue. Repeated methanol triturations with soni-
cation gave a cream coloured powder when filtered (205 mg,
1-(1H-Benzoimidazol-5-yl)-1,2,3,12b-tetrahydroimidazo[1,2-f]
phenanthridine (3)
To a solution of BEP (700 mg, 1 eq) in methanol (50 mL) was
added 5-aminobenzimidazole (254 mg, 1 eq) and triethylamine
(797 μL, 3 eq) and stirred at room temperature. An orange sol-
ution immediately formed, then after 1 h a peach/orange suspen-
sion developed. The suspension was filtered and washed with
fresh methanol. Precipitate formed in the methanol filtrate, and
was more clean TIP (260 mg, 40%). 1H NMR (DMSO,
400 MHz): δ 12.02 (s, 1H), δ 8.02 (brd, 1H), δ 7.93 (d, 1H, J =
7.6 Hz), δ 7.85 (d, 1H, J = 7.6 Hz), δ 7.50 (brd, 1H), δ 7.40 (t,
1H, J = 7.4 Hz), δ 7.32 (t, 1H, J = 7.4 Hz), δ 7.24 (t, 1H, J = 7.4
Hz), δ 7.04 (d, 1H, J = 7.6 Hz), δ 7.00 (t, 1H, J = 7.4 Hz), δ
6.89 (d, 1H, J = 8 Hz), δ 6.77 (d, 2H, J = 8 Hz), δ 5.26 (s, 1H),
δ 4.07 (m, 1H), δ 3.83 (t, 1H, J = 7.6 Hz), δ 3.70 (t, 1H, J = 7.6
Hz), δ 3.32 (hidden under DMSO peak, 1H); 13C NMR (DMSO,
100 MHz): δ 143.4 (C × 2), δ 133.9 (C × 2), δ 131.6 (C × 2), δ
129.3 (CH), δ 127.7 (CH), δ 126.9 (CH), δ 124.2 (CH), δ 123.6
(CH), δ 123.3 (C), δ 123.2 (CH), δ 119.5 (CH), δ 113.0 (CH), δ
75.1 (CH), δ 52.1 (CH2), δ 44.4 (CH2); MS (FAB) for
(C22H19N4) (M + H+) 338.7 (12), 231 (9), 157 (40), 80 (100);
HRMS (1312) (FAB) for (C22H19N4) (M + H+) calculated
339.1610, found 339.1609.
1
38%). H NMR (CDCl3, 400 MHz): δ 7.89 (d, 1H, J = 7.6 Hz),
δ 7.80 (d, 1H, J = 7.6 Hz), δ 7.42 (t, 1H, J = 7.4 Hz), δ 7.35 (m,
6H), δ 7.05 (t, 1H, J = 7.5 Hz), δ 6.85 (d, 1H, J = 7.8 Hz), δ
6.70 (d, 1H, J = 7.6 Hz), δ 5.43 (s, 1H), δ 4.17 (q, 1H, J = 8.3
Hz), δ 4.01 (t, 1H, J = 8.2 Hz), δ 3.69 (t, 1H, J = 7.2 Hz), δ 3.41
(q, 1H, J = 8.5 Hz), δ 2.79 (s, 3H); 13C NMR (CDCl3,
100 MHz): δ 165.7 (C), δ 155.5 (C), δ 149.1 (C), δ 143.4 (C), δ
135.5 (C), δ 134.2 (C), δ 131.9 (CH), δ 129.4 (CH), δ 129.2
(CH), δ 127.9 (CH), δ 127.3 (CH), δ 124.4 (CH), δ 124.3 (C), δ
123.8 (CH), δ 123.5 (CH), δ 120.0 (CH), δ 116.4 (CH), δ 113.7
(CH), δ 113.0 (CH), δ 112.5 (CH), δ 112.3 (CH), δ 75.0 (CH), δ
51.1 (CH2), 44.9 (CH2), δ 19.4 (CH3); IR (Goldengate, cm−1):
3107 (w), 2875 (w), 2838 (w), 1600 (m), 1446 (m), 1319 (m),
1170 (m), 750 (s); MS (EI+) for (C25H21N3S) (M) 395.1 (30),
193 (100), 165 (20), 91 (85); HRMS (EI+) for (C25H21N3S)
(M+) calculated 395.1456, found 395.1458.
1-[3-(2-Methyl-thiazol-4-yl)-phenyl]-2,3-dihydro-1H-imidazo
[1,2-f]phenanthridin-4-ylium bromide (6)
To a suspension of 5-bromoethylphenanthridinium (386 mg, 1
eq) in chloroform (20 mL) was added 4-(3-aminophenyl)-2-
methylthiazole (200 mg, 1 eq) and triethylamine (431 μL, 3 eq)
and stirred at room temperature under N2 until a solution formed
after 1 h. The reaction mixture was washed with water, brine,
dried over MgSO4 and concentrated under vacuum, giving a
light brown honeycomb like residue, which was dissolved in
ethyl acetate and NBS (186 mg, 1 eq) added and stirred for 2 h
1-(1H-Benzoimidazol-5-yl)-2,3-dihydro-1H-imidazo[1,2-f]
phenanthridin-4-ylium bromide (4)
To a suspension of BEP (700 mg, 1 eq) in chloroform (50 mL)
was added 5-aminobenzimidazole (254 mg, 1 eq) and triethyl-
amine (797 μL, 3 eq) and stirred at room temperature going to a
solution and then to a suspension after 20 min. The suspension
was filtered and the residue dissolved in ethyl acetate. NBS
(339 mg, 1eq) was added and stirred, creating a murky yellow
suspension. This was filtered, washed with diethyl ether and
dried. Precipitate had formed in the ethyl acetate filtrate, so this
was filtered and dried (429 mg, 54%). 1H NMR (DMSO,
400 MHz): δ 8.90 (d, 1H, J = 8 Hz), δ 8.82 (d, 1H, J = 8 Hz), δ
8.48 (s, 1H), δ 8.02 (t, 1H, J = 7.2 Hz), δ 7.94 (t, 2H, J = 7.4
Hz), δ 7.97 (broad m, 2H), δ 7.71 (t, 1H, J = 7.4 Hz), δ 7.55
(brd, 1H), δ 7.47 (t, 1H, J = 7.8 Hz), δ 7.24 (d, 1H, J = 7.6 Hz),
δ 4.96 (t, 2H, J = 10.4 Hz), δ 4.66 (m, 2H); 13C NMR (DMSO,
100 MHz): δ 152.7 (C), δ 144.6 (CH), δ 135.2 (CH × 2), δ
135.0 (C), δ 133.1 (C), δ 132.7 (C), δ 131.5 (CH), δ 128.6 (CH),
δ 127.1 (CH), δ 125.6 (CH), δ 124.2 (CH), δ 124.1 (CH × 2), δ
120.5 (CH), δ 120.3 (C), δ 116.1 (CH), δ 115.5 (C), δ 55.1
(CH2), δ 46.8 (CH2); IR (Goldengate, cm−1): 3054 (w), 2729
(w), 1774 (w), 1705 (m), 1543 (s), 1312 (m), 1173 (m), 754 (s);
MS (FAB) for (C22H17N4) (M+) 337 (100), 180 (10); HRMS
1
and then filtered (480 mg, 96%). H NMR (DMSO, 400 MHz):
δ 9.14 (d, 1H, J = 16.4 Hz), δ 8.93 (d, 1H, J = 8.0 Hz), δ 8.84
(d, 1H, J = 8.0 Hz), δ 8.21 (d, 1H, J = 7.6 Hz), δ 8.12 (s, 1H), δ
8.05 (t, 1H, J = 7.4 Hz), δ 7.94 (t, 1H, J = 7.6 Hz), δ 7.86 (d,
1H, J = 8.0 Hz), δ 7.73 (m, 3H), δ 7.55 (t, 1H, J = 7.8 Hz), δ
7.39 (d, 1H, J = 8.4 Hz), δ 4.96 (t, 2H, J = 10.2 Hz), δ 4.67 (m,
2H), δ 2.68 (s, 3H); 13C NMR (DMSO, 100 MHz) (only 12
CH): δ 116.2 (C), δ 152.6 (C), δ 152.1 (C), δ 139.8 (C), δ 136.6
(C), δ 135.3 (CH), δ 135.1 (C), δ 132.6 (C), δ 131.6 (CH), δ
131.3 (CH), δ 128.7 (CH), δ 127.2 (CH), δ 127.1 (CH), δ 126.0
(CH), δ 125.8 (CH), δ 124.3 (CH), δ 124.1 (CH), δ 120.4 (C), δ
116.2 (CH), δ 115.7 (C), δ 115.3 (CH), δ 54.4 (CH2), δ 47.0
(CH2), δ 18.9 (CH3); MS (FAB) for (C25H20N3S) (M+) 394 (91),
232 (62), 179 (20), 158 (100), 138 (20), 81 (100), 80 (33);
HRMS (FAB) for (C25H20N3S) (M+) calculated 394.1378, found
394.1382.
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 2026–2034 | 2031

View Online
5-[2-([1,10]Phenanthrolin-5-ylamino)-ethyl]phenanthridinium
bromide (7)
suspension was filtered and washed with acetone (305 mg,
53%). H NMR (DMSO, 400 MHz): δ 10.07 (s, 1), δ 9.26 (m,
1
1H), δ 9.17 (d, 1H, J = 8.4 Hz), δ 8.72 (m, 1H), δ 8.40 (t, 1H, J
= 6.8 Hz), δ 8.37 (d, 1H, J = 7.2 Hz), δ 8.15 (m, 2H), δ 8.09 (d,
1H, J = 6.8 Hz), δ 8.03 (t, 1H, J = 7.6 Hz), δ 7.99 (d, 1H, J =
7.2 Hz), δ 7.88 (t, 1H, J = 9.2 Hz), δ 7.87 (d, 2H, J = 8.4 Hz), δ
7.52 (t, 1H, J = 7.6 Hz), δ 7.35 (t, 1H, J = 10.6 Hz), δ 7.27 (t,
1H, J = 7.4 Hz), δ 7.03 (t, 1H, J = 5.8 Hz), δ 6.80 (d, 1H, J =
7.6 Hz), δ 5.39 (t, 2H, J = 4.4 Hz), δ 4.10 (q, 2H); 13C NMR
(DMSO, 100 MHz): δ 155.7 (CH), δ 144.9 (C), δ 139.1 (C), δ
138.0 (CH), δ 137.3 (C), δ 135.8 (C), δ 134.5 (C), δ 133.4 (C), δ
132.6 (CH), δ 132.0 (CH), δ 130.3 (CH), δ 130.2 (CH), δ 127.4
(CH), δ 126.0 (C), δ 125.7 (CH), δ 125.1 (CH), δ 125.0 (CH), δ
124.2 (C), δ 123.5 (C X 2), δ 123.3 (CH), δ 123.1 (CH), δ 121.5
(CH), δ 121.2 (CH), δ 120.6 (C), δ 120.4 (CH), δ 120.0 (CH), δ
119.8 (CH), δ 104.4 (CH), δ 56.4 (CH2), δ 41.8 (CH2); IR
(Goldengate, cm−1): 3397 (w), 3016 (w), 1627 (m), 1533 (m),
1429 (s), 1263 (m), 782 (s); MS (FAB) for (C31H23N2) (M+) 423
(100), 307 (7), 244 (15), 180 (17); HRMS (FAB) for (C31H23N2)
(M+) calculated 423.1861, found 423.1856.
To a suspension of BEP (752 mg, 1 eq) in chloroform (70 mL)
was added 1,10-phenathrolin-5-amine (400 mg, 1 eq) and tri-
ethylamine (854 μL, 3 eq) and stirred at room temperature as an
orange suspension for 4 days and then filtered as an orange
1
powder (320 mg, 32%). H NMR (DMSO, 400 MHz): δ 10.03
(s, 1H), δ 9.20 (m, 1H), δ 9.11 (d, 1H, J = 8.4 Hz), δ 9.05 (d,
1H, J = 4 Hz), δ 8.79 (m, 1H), δ 8.75 (d, 1H, J = 2.8 Hz), δ 8.37
(t, 1H, J = 7.8 Hz), δ 8.33 (m, 2H), δ 8.14 (m, 2H), δ 8.06 (d,
1H, J = 6.8 Hz), δ 8.01 (t, 1H, J = 7.6 Hz), δ 7.65 (q, 1H), δ
7.57 (q, 1H), δ 6.95 (s, 1H), δ 6.73 (t, 1H, J = 6 Hz), δ 5.43 (t,
2H, J = 5.2 Hz), δ 4.12 (m, 2H); 13 C NMR (DMSO,
100 MHz): δ 155. 8 (CH), δ 149.4 (CH), δ 146.2 (C), δ 145.5
(CH), δ 140.8 (C), δ 140.2 (C), δ 138.0 (CH), δ 134.5 (C), δ
133.4 (C), δ 133.3 (CH), δ 132.5 (CH), δ 132.0 (CH), δ 130.3
(CH), δ 130.3 (C), δ 130.2 (CH), δ 129.6 (CH), δ 126.0 (C), δ
125.1 (CH), δ 123.5 (C), δ 123.3 (CH), δ 123.1 (CH), δ 122.2
(CH), δ 121.9 (C), δ 119.8 (CH), δ 99.1 (CH), δ 56.1 (CH2), δ
41.6 (CH2); IR (KBr, cm−1): 3227 (w), 3060 (w), 2936 (w),
1626 (m), 1533 (m), 1163 (m), 838 (m), 759 (s); MS (FAB) for
(C27H21N4 ) (M+) 401 (45), 222 (40), 180 (22), 157 (80), 79
+
1-(2-Ethynyl-phenyl)-2,3-dihydro-1H-imidazo[1,2-f]
phenanthridin-4-ylium bromide (10)
+
(100); HRMS (FAB) for (C27H21N4 ) (M+) calculated 401.1766,
found 401.1772
To a suspension of BEP (700 mg, 1 eq) in chloroform (50 mL)
was added 2-ethynylaniline (217 μL, 1 eq) and triethylamine
(797 μL, 3 eq) and stirred at room temperature for 4.5 h when a
solution formed. The solution was washed with water and brine
then concentrated under vacuum to a dark orange oil. Acetone
was added to the oil, initially creating a solution but on standing
for 18 h a precipitate formed which was filtered and collected as
an orange static powder (624 mg, 82%). 1H NMR (DMSO,
400 MHz): δ 8.97 (d, 1H, J = 6.8 Hz), δ 8.86 (d, 1H, J = 6.4
Hz), δ 8.10 (t, 1H, J = 6 Hz), δ 7.96 (t, 1H, J = 6.2 Hz), δ 7.87
(m, 3H), δ 7.77 (t, 1H, J = 5.6 Hz), δ 7.75 (t, 1H, J = 7 Hz), δ
7.72 (t, 1H, J = 6.2 Hz), δ 7.60 (t, 1H, J = 6.2 Hz), δ 7.21 (d,
1H, J = 6.8 Hz), δ 5.13 (m, 1H), δ 5.04 (m, 1H), δ 4.62 (m, 2H),
δ 4.49 (s, 1H); 13C NMR (DMSO, 100 MHz): δ 152.8 (C), δ
140.5 (C), δ 135.7 (CH), δ 134.9 (C), δ 134.4 (CH), δ 132.3 (C),
δ 131.7 (CH), δ 130.7 (CH), δ 129.1 (CH), δ 128.1 (CH), δ
126.2 (CH), δ 126.1 (CH), δ 124.5 (CH), δ 124.2 (CH), δ 120.5
(C), δ 120.2 (C), δ 116.6 (CH), δ 115.2 (C), δ 87.7 (C), δ 78.2
(CH), δ 53.3 (CH2), δ 47.3 (CH2); IR (Goldengate, cm−1): 3467
(w), 3130 (w), 1706 (w), 1575 (m), 1524 (s), 1301 (m), 785 (s);
MS (FAB) for (C23H17N2) 321.4 (M+) (100), 319.3 (7), 137.2
(8); HRMS (FAB) for (C23H17N2) (M+) calculated 321.1392,
found 321.1395.
1-(9H-Fluoren-2-yl)-1,2,3,12b-tetrahydroimidazo[1,2-f]
phenanthridine (8)
To a suspension of BEP (700 mg, 1 eq) in chloroform (70 mL)
was added 2-aminofluorene (345.6 mg, 1 eq) and triethylamine
(1 mL, excess) and stirred at room temperature for 30 min, when
a solution had developed. The solution was washed with water
and then brine, then concentrated under vacuum to an orange
residue, and a methanol trituration yielded a pale yellow powder
1
(666 mg, 90%). H NMR (DMSO, 400 MHz): δ 7.95 (d, 1H, J
= 7.6 Hz), δ 7.88 (d, 1H, J = 7.6 Hz), δ 7.75 (m, 2H), δ 7.51 (d,
1H, J = 7.2 Hz), δ 7.44 (t, 1H, J = 7.6 Hz), δ 7.31(m, 2H), δ
7.20 (t, 1H, J = 7.2 Hz), δ 7.03 (m, 2H), δ 6.91 (d, 1H, J = 7.2
Hz), δ 6.76 (d, 1H, J = 7.6 Hz), δ 5.34 (s, 1H), δ 4.03 (m, 1H), δ
3.93 (t, 1H, J = 8 Hz), δ 3.86 (s, 2H), δ 3.72 (t, 1H, J = 7.8 Hz);
13C NMR (DMSO, 100 MHz): δ 148.1 (C), δ 144.4 (C), δ 143.2
(C), δ 142.0 (C), δ 141.6 (C), δ 133.8 (C), δ 131.6 (C), δ 131.5
(C), δ 129.3 (CH), δ 127.7 (CH), δ 126.9 (CH), δ 126.6 (CH), δ
125.0 (CH), δ 124.8 (CH), δ 123.9 (CH), δ 123.6 (CH), δ 123.3
(CH), δ 123.3 (C), δ 120.4 (CH), δ 119.6 (CH), δ 118.6 (CH), δ
113.1 (CH), δ 113.0 (CH), δ 110.9 (CH), δ 74.6 (CH), δ 51.2
(CH2), δ 44.4 (CH2), δ 36.5 (CH2); IR (Goldengate, cm−1): 3057
(w), 2962 (w), 2836 (w), 2766 (w), 1611 (m), 1453 (m), 1210
(m), 711 (s); MS (FAB) for (C28H23N2) (M + H)+ 387.5 (16),
232 (32), 179 (21), 157 (71), 80 (100); HRMS (FAB) for
(C28H23N2) (M + H)+ calculated 387.1861, found 387.1855.
1-(5-Chloro-pyridin-2-yl)-2,3-dihydro-1H-imidazo[1,2-f]
phenanthridin-4-ylium bromide (11)
To a suspension of BEP (500 mg, 1 eq) in chloroform (50 mL)
was added 2-amino-5-chloropyridine (175 mg, 1 eq) and tri-
ethylamine (570 μL, 3 eq) and stirred at room temperature. The
suspension became a solution after 2 h 40 min, and was washed
with water, brine then concentrated under vacuum to an orange
residue. An acetone trituration yielded a yellow precipitate
5-[2-(Fluoranthen-3-ylamino)-ethyl]phenanthridinium bromide
(9)
BEP (500 mg, 1 eq) was suspended in chloroform (50 mL) and
stirred with 3-aminofluoranthene (296 mg, 1 eq) and triethyl-
amine (570 μL, 3 eq) at room temperature for 5 h. The
1
(251 mg, 45%). H NMR (DMSO, 400 MHz): δ 9.51 (brd, 1H),
2032 | Org. Biomol. Chem., 2012, 10, 2026–2034
This journal is © The Royal Society of Chemistry 2012

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δ 8.98 (d, 1H, J = 6.8 Hz), δ 8.91 (d, 1H, J = 6.4 Hz), δ 8.71 (d,
1H, J = 2 Hz), δ 8.26 (dd, 1H), δ 8.15 (t, 1H, J = 5.8 Hz), δ 7.96
(m, 2H), δ 7.80 (t, 1H, J = 6 Hz), δ 7.74 (d, 1H, J = 7.2 Hz), δ
7.68 (t, 1H, J = 6 Hz), δ 7.55 (d, 1H, J = 6.8 Hz), δ 5.05 (d, 2H,
J = 8 Hz), δ 4.73 (d, 2H, J = 8 Hz); 13C NMR (DMSO,
100 MHz): δ 152.6 (C), δ 150.8 (C), δ 148.0 (CH), δ 139.7
(CH), δ 135.9 (CH), δ 135.3 (C), δ 132.2 (C), δ 131.7 (CH),
δ 130.9 (C), δ 128.8 (CH), δ 128.2 (CH), δ 126.6 (CH),
δ 124.3 (CH), δ 124.2 (CH), δ 121.2 (C), δ 121.0 (CH),
δ 116.9 (CH), δ 115.1 (C), δ 52.1 (CH2), δ 47.7 (CH2); IR (KBr,
cm−1): 3440 (m), 3393 (m), 2975 (m), 2935 (m), 2736 (m),
2674 (m), 2491 (m), 1573 (s), 1304 (s), 1112 (m), 857 (m); MS
(FAB) for (C20H15N3Cl) (M+) 332 (28), 107 (100); HRMS
(FAB) for (C20H15N3Cl) (M+) calculated 332.0955, found
332.0952.
(CH), δ 140.2 (CH), δ 135.8 (CH), δ 135.2 (C), δ 132.2 (C), δ
131.7 (CH), δ 128.6 (CH), δ 127.9 (CH), δ 126.4 (CH), δ 124.7
(CH), δ 124.3 (CH), δ 124.2 (CH), δ 121.04 (C), δ 120.0 (CH),
δ 116.8 (CH), δ 115.2 (C), δ 52.2 (CH2), δ 47.5 (CH2); IR
(Goldengate, cm−1): 3415 (w), 3061 (w), 1647 (w), 1580 (m),
1309 (m), 1172 (w), 1038 (w), 753 (s); MS (FAB) for
(C20H16N3) (M+) 298 (100), 179 (14), 107 (27); HRMS (FAB)
for (C20H16N3) (M+) calculated 298.1344, found 298.1339.
1-(2-Hydroxy-phenyl)-2,3-dihydro-1H-imidazo[1,2-f]
phenanthridin-4-ylium bromide (14)
To a round bottomed flask a solution of BEP (500 mg, 1 eq) and
2-aminophenol (149 mg, 1 eq) with triethylamine (570 μL, 3 eq)
and chloroform (40 mL) was added and stirred at room tempera-
ture for 2.5 h. This created a creamy suspension which was
filtered and collected to yield the product as a white powder
(210 mg, 49%). 1H NMR (DMSO, 400 MHz): δ 10.52 (s, 1H), δ
8.94 (d, 1H, J = 8.4 Hz), δ 8.83 (d, 1H, J = 8.0 Hz), δ 8.09 (t,
1H, J = 7.6 Hz), δ 7.94 (t, 1H, J = 7.6 Hz), δ 7.85 (d, 1H, J =
8.4 Hz), δ 7.73 (t, 1H, J = 7.8 Hz), δ 7.64 (d, 1H, J = 8.4 Hz), δ
7.60 (d, 1H, J = 7.6 Hz), δ 7.50 (t, 2H, J = 9.4 Hz), δ 7.17 (d,
1H, J = 8.0 Hz), δ 7.11 (t, 1H, J = 7.6 Hz), δ 5.05 (q, 1H, J =
10.8 Hz), δ 4.94 (q, 1H, J = 10.8 Hz), δ 4.53 (t, 2H, J = 10.4
Hz); 13C NMR (DMSO, 100 MHz): δ 153.0 (C), δ 152.9 (C), δ
135.5 (CH), δ 134.7 (C), δ 132.5 (C), δ 131.7 (CH), δ 131.6
(CH), δ 129.0 (CH), δ 128.2 (CH), δ 126.0 (CH), δ 125.8 (CH),
δ 125.6 (C), δ 124.3 (CH), δ 124.1 (CH), δ 120.7 (CH), δ 120.2
(C), δ 117.7 (CH), δ 116.3 (CH), δ 115.6 (C), δ 52.9 (CH2), δ
46.7 (CH2); IR (Goldengate, cm−1): 2947 (w), 1613 (w), 1577
(m), 1486 (m), 1449 (w), 1393 (w), 1313 (m), 1240 (w), 1171
(w), 1153 (w), 1118 (w), 993 (w), 872 (w), 785 (w), 747 (s); MS
(FAB): 313 (M+) (15), 157 (60), 80 (100).
1-(6-Chloro-pyridin-3-yl)-2,3-dihydro-1H-imidazo[1,2-f]
phenanthridin-4-ylium bromide (12)
To a round bottomed flask a solution of BEP (286 mg, 1 eq) and
5-amino-2-chloropyridine (100 mg, 1 eq) with triethylamine
(325 μL, 3 eq) and chloroform (25 mL) was added and stirred at
room temperature for 4 h. The resulting solution was washed
with water and brine and was then concentrated under vacuum to
form a red/brown residue. The residue was then triturated in
1
acetone to yield the product as a yellow solid (40 mg, 15%). H
NMR (DMSO, 400 MHz): δ 8.97 (d, 1H, J = 6.8 Hz), δ 8.88 (d,
1H, J = 6.8 Hz), δ 8.80 (d, 1H, J = 2.4 Hz), δ 8.23 (dd, 1H, J =
2.4,7.2 Hz), δ 8.12 (t, 1H, J = 6.0 Hz), δ 7.96 (t, 1H, J = 6.2
Hz), δ 7.88 (t, 2H, J = 8.4 Hz), δ 7.77 (t, 1H, J = 6.0 Hz), δ 7.67
(t, 1H, J = 6.0 Hz), δ 7.49 (d, 1H, J = 6.8 Hz), δ 4.99 (t, 2H, J =
8.2 Hz), δ 4.66 (t, 2H, J = 8.0 Hz); 13C NMR (DMSO,
100 MHz): δ 153.0 (C), δ 150.4 (C), δ 148.0 (CH), δ 138.0
(CH), δ 136.2 (C), δ 135.6 (CH), δ 135.1 (C), δ 132.3 (C), δ
131.6 (CH), δ 129.1 (CH), δ 127.3 (CH), δ 126.2 (CH), δ 126.1
(CH), δ 124.5 (CH), δ 124.1 (CH), δ 120.8 (C), δ 116.5 (CH), δ
114.9 (C), δ 54.2 (CH2), δ 47.4 (CH2); IR (Goldengate, cm−1):
3019 (w), 1615 (w), 1577 (s), 1544 (m), 1527 (m), 1458 (m),
1451 (m), 1375 (w), 1311 (s), 1176 (w), 1108 (s), 935 (w), 844
(w), 761 (s); MS (FAB): 332 (M+) (20), 179 (30), 157 (30), 80
(100).
1-(4-Hydroxy-pyridin-3-yl)-2,3-dihydro-1H-imidazo[1,2-f]
phenanthridin-4-ylium bromide (15)
To a suspension of BEP (850 mg, 2.32 eq) in chloroform
(70 mL) was added 3-amino-4-hydroxypyridine (150 mg, 1 eq)
and triethylamine (570 μL, 3 eq) and stirred for 2.5 h. The sus-
pension was filtered and washed with acetone (278 mg, 56%).
1H NMR (DMSO, 400 MHz): δ 8.90 (d, 1H, J = 6.4 Hz), δ 8.82
(d, 1H, J = 6.4 Hz), δ 8.48 (s, 1H), δ 8.09 (t, 1H, J = 6.4 Hz), δ
8.06 (d, 1H, J = 6.8 Hz), δ 7.94 (t, 1H, J = 5.4 Hz), δ 7.92 (d,
1H, J = 6 Hz), δ 7.83 (d, 1H, J = 6 Hz), δ 7.73 (t, 1H, J = 6 Hz),
δ 7.68 (t, 1H, J = 6.2 Hz), δ 6.40 (d, 1H, J = 9 Hz), δ 5.10 (m,
1H), δ 4.83 (m, 1H), δ 4.59 (m, 1H), δ 4.23 (q, 1H); 13C NMR
(DMSO, 100 MHz): δ 171.7 (C), δ 154.0 (C), δ 139.2 (CH), δ
137.9 (CH), δ 135.5 (CH), δ 134.1 (C), δ 132.3 (C), δ 131.5
(CH), δ 129.3 (C), δ 129.1 (CH), δ 126.0 (CH), δ 126.0 (CH), δ
124.1 (CH), δ 124.0 (CH), δ 120.5 (C), δ 117.8 (CH), δ 116.5
(CH), δ 116.1 (C), δ 53.4 (CH2), δ 46.6 (CH2); IR (Goldengate,
cm−1): 3494 (w), 3056 (w), 2817 (w), 1642 (m), 1579 (s), 1312
(m), 784 (m), 717 (s); MS (FAB) for (C20H16N3O) (M+) 314
(100), 78 (10), 36 (24); HRMS (FAB) for (C20H16N3O) (M+)
calculated 314.1293, found 314.1289.
1-Pyridin-2-yl-2,3-dihydro-1H-imidazo[1,2-f]phenanthridin-4-
ylium bromide (13)
To a suspension of BEP (500 mg, 1 eq) in chloroform (50 mL)
was added 2-aminopyridine (94 mg, 1 eq) and triethylamine
(570 μL, 3 eq) and stirred at room temperature for 4 h, when a
solution had formed. It was washed with water, brine and con-
centrated under vacuum to an orange residue, then an acetone tri-
turation yielded a yellow powder (150 mg, 29%). 1H NMR
(DMSO, 400 MHz): δ 8.97 (d, 1H, J = 6.4 Hz), δ 8.89 (d, 1H, J
= 6 Hz), δ 8.65 (d, 1H, J = 4 Hz), δ 8.14 (t, 1H, J = 6.6 Hz), δ
8.12 (t, 1H, J = 6.2 Hz), δ 7.97 (q, 1H), δ 7.94 (t, 1H, J = 6 Hz),
δ 7.79 (t, 1H, J = 5.6 Hz), δ 7.72 (d, 1H, J = 6.4 Hz), δ 7.64 (d,
1H, J = 4.4 Hz), δ 7.63 (t, 1H, J = 2.8 Hz), δ 7.37 (d, 1H, J =
6.4 Hz), δ 5.04 (t, 2H, J = 8 Hz), δ 4.73 (t, 2H, J = 8 Hz); 13C
NMR (DMSO, 100 MHz): δ 152.7 (C), δ 152.1 (C), δ 149.7
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(FAB) for (C20H18N3O) (M+) 316 (53), 183 (18), 151 (17), 114
(14), 78 (53), 61 (100), 38 (36), 36 (26); HRMS (FAB) for
(C20H18N3O) (M+) calculated 316.1450, found 316.1446.
5-[2-(3-Hydroxy-pyridin-2-ylamino)-ethyl]-phenanthridinium
bromide (16)
To a suspension of BEP (500 mg, 1 eq) in chloroform (50 mL)
was added 2-amino-3-hydroxypyridine (112.5 mg, 1 eq) and tri-
ethylamine (570 μL, 3 eq) and stirred at room temperature for
20 h, then filtered. A further 89 mg of BEP was added, and then
Notes and references
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2777–2812.
1
filtered to give the product (230 mg, 43%). H NMR (DMSO,
2 K. Morohashi, A. Yoshino, A. Yoshimori, S. Saito, S. Tanuma,
K. Sakaguchi and F. Sugawara, Biochem. Pharmacol., 2005, 70, 37–46.
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5 M. J. Coghlan, W. R. Arnold and B. A. Caley, Pestic. Sci., 1990, 29, 67–
73.
400 MHz): δ 10.07 (s, 1H), δ 9.71 (s, 1H), δ 9.2 (d, 1H, J = 6
Hz), δ 9.14 (d, 1H, J = 6.4 Hz), δ 8.85 (d, 1H, J = 6.4 Hz), δ
8.53 (d, 1H, J = 6.4 Hz), δ 8.39 (t, 1H, J = 6.2 Hz), δ 8.17 (t,
1H, J = 5.8 Hz), δ 8.12 (t, 1H, J = 6 Hz), δ 8.07 (t, 1H, J = 6
Hz), δ 7.23 (d, 1H, J = 2.8 Hz), δ 6.75 (d, 1H, J = 5.2 Hz), δ
6.35 (t, 1H, J = 5 Hz), δ 5.23 (t, 2H, J = 4.4 Hz), δ 3.99 (q, 2H);
13C NMR (DMSO, 100 MHz): δ 155.3 (CH), δ 148.8 (C), δ
139.6 (C), δ 137.8 (CH), δ 136.6 (CH), δ 134.4 (C), δ 133.8 (C),
δ 132.6 (CH), δ 131.8 (CH), δ 130.5 (CH), δ 130.1 (CH), δ
125.9 (C), δ 124.8 (CH), δ 123.5 (C), δ 123.0 (CH), δ 120.0
(CH), δ 117.7 (CH), δ 112.1 (CH), δ 57.8 (CH2), δ 45.6 (CH2);
IR (KBr, cm−1): 3426 (m), 3058 (w), 2960 (w), 2675 (w), 1613
(m), 1504 (m), 1174 (m), 1087 (m), 871 (w), 754 (s); MS (FAB)
for (C20H18N3O) (M+) 316 (100), 195 (9), 183 (23), 107 (13);
HRMS (FAB) for (C20H18N3O) (M+) calculated 316.1450,
found 316.1446.
6 M. Duksi, D. Baretic, V. Caplar and I. Piantanida, Eur. J. Org. Chem.,
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R. Brown and L. Cronin, J. Med. Chem., 2005, 48, 4504–4506.
9 A. D. C. Parenty and L. Cronin, Synthesis, 2008, 155–160.
10 T. Nakanishi, A. Masuda, M. Suwa, Y. Akiyama, N. Hoshino-Abe and
M. Suzuki, Bioorg. Med. Chem. Lett., 2000, 10, 2321–2323.
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1999, 62, 864–867.
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L. Cronin, ChemBioChem, 2006, 1757–1763.
13 L. V. Smith, J. M. de la Fuente, K. M. Guthrie, A. D. C. Parenty and
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Am. Chem. Soc., 2008, 130, 13059–13065.
5-[2-(2-Hydroxy-pyridin-3-ylamino)-ethyl]phenanthridinium
bromide (17)
To a suspension of BEP (500 mg, 1 eq) in chloroform (50 mL)
was added 3-amino-2-hydroxypyridine (150 mg, 1 eq) and tri-
ethylamine (570 μL, 3 eq) and stirred for 3.5 h. The suspension
17 C. J. Richmond, Applications for Imidazophenanthridine-based Hetero-
cycles, University of Glasgow, 2009.
18 D. L. Jakeman, S. Farrell, W. Young, R. J. Doucet and S. C. Timmons,
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M. Antonov, ChemPhysChem, 2011, 12, 1747–1755.
24 B. R. T. Keene, P. Tissington, Recent Developments in Phenanthridine
Chemistry, in Advances in Heterocyclic Chemistry, A. R. Katritzky and
A. J. Boulton, ed. Academic Press, 1971, Vol. 13, pp 315–413.
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1
was filtered and washed with acetone (349 mg, 65%). H NMR
(DMSO, 400 MHz): δ 11.35 (s, 1H), δ 10.04 (s, 1H), δ 9.21 (d,
1H, J = 5.2 Hz), δ 9.16 (d, 1H, J = 6.4 Hz), δ 8.69 (d, 1H, J =
7.2 Hz), δ 8.56 (d, 1H, J = 6 Hz), δ 8.42 (t, 1H, J = 5.8 Hz), δ
8.13 (m, 3H), δ 6.62 (brd, 1H), δ 6.37 (t, 1H, J = 5.6 Hz), δ 6.03
(t, 1H, J = 5.4 Hz), δ 5.92 (t, 1H, J = 5.4 Hz), δ 5.20 (t, 2H, J =
4.4 Hz), δ 3.78 (q, 2H); 13C NMR (DMSO, 100 MHz): δ 157.3
(C), δ 155.6 (CH), δ 137.9 (CH), δ 137.7 (C), δ 134.5 (C), δ
133.5 (C), δ 132.8 (CH), δ 131.9 (CH), δ 130.3 (CH), δ 130.2
(CH), δ 125.9 (C), δ 124.94 (CH), δ 123.5 (C), δ 123.1 (CH), δ
119.9 (CH), δ 119.8 (CH), δ 107.2 (CH), δ 105.9 (CH), δ 56.1
(CH2), δ 41.2 (CH2); IR (KBr, cm−1): 3280 (w), 2985 (w), 1726
(w), 1627 (m), 1448 (m), 1259 (m), 1128 (m), 749 (s); MS
26 A. Molinos-Gómez, X. Vidal, M. Maymó, D. Velasco, J. Martorell and
F. López-Calahorra, Tetrahedron, 2005, 61, 9075–9081.
2034 | Org. Biomol. Chem., 2012, 10, 2026–2034
This journal is © The Royal Society of Chemistry 2012