Fine tuning reactivity: Synthesis and isolation of 1,2,3,12b- tetrahydroimidazo[1,2-f]phenanthridines

Article abstract of DOI:10.1021/jo901622e

(Figure Presented) A facile route for the synthesis and isolation of 1,2,3,12b-tetrahydroimidazo[1,2-f]phenanthridines (TIPs) has been developed. The heterocycle is a reactive intermediate in the three-step cascade synthesis of 2,3-dihydro-1H-imidazo[1,2-

Full text of DOI:10.1021/jo901622e

pubs.acs.org/joc
Fine Tuning Reactivity: Synthesis and Isolation of 1,2,3,12b-
Tetrahydroimidazo[1,2-f ]phenanthridines
Craig J. Richmond, Roslyn M. Eadie, Alexis D. C. Parenty, and Leroy Cronin*
WestCHEM, Department of Chemistry, University of Glasgow, Glasgow G12 8QQ, United Kingdom
l.cronin@chem.gla.ac.uk
Received August 3, 2009
A facile route for the synthesis and isolation of 1,2,3,12b-tetrahydroimidazo[1,2-f]phenanthridines
(TIPs) has been developed. The heterocycle is a reactive intermediate in the three-step cascade
synthesis of 2,3-dihydro-1H-imidazo[1,2-f]phenanthridinium cations (DIPs), a biologically active
DNA intercalating framework; however, the intermediate has previously only been characterized in
situ. Derivatization of the structure at the imidazo-N position controls the reactivity of the
intermediate with respect to electronic potential and pKa allowing isolation of a selection of TIP
structures. Correlations between these parameters and reaction outcome have been made, and other
influences such as steric and solvent effects have also been investigated.
Introduction
may possess advantageous therapeutic activities or chemical
reactivity.6-11
Nitrogen-containing heterocycles are prevalent in medi-
cinal chemistry due to the fact that many natural and
synthetic biologically active compounds share this common
architectural feature.1-5 The number and structural diversity
of heterocyclic motifs are great. However the discovery and
synthesis of new classes of heterocycles, especially if the
synthetic methodology is modular and reliable, is always a
welcome addition as it offers routes to new substrates which
A family of nonplanar aromatic heterocycles with attrac-
tive chemical and biological activities has been synthesized:
1,2,3,12b-tetrahydroimidazo[1,2-f]phenanthridines (TIPs)
are sensitive to both changes in pH and electrochemical
potential, two very important biological stimuli.12-16 There
are a large number of other structurally similar heterocycles
reported, but to the best of our knowledge there are currently
no examples for the isolation of heterocycles containing the
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Published on Web 10/06/2009
DOI: 10.1021/jo901622e
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2009 American Chemical Society

Richmond et al.
JOCArticle
SCHEME 1. Mechanism for DIP Synthesis from BEP via TIP Intermediate
N-substituted TIP motif.17-23 The majority of these similarly
nonplanar heterocycles exhibit high levels of biological
activity and have applications as antibacterials, fungicides,
anticancer therapeutics, and other bioactive agents.24-29
Compounds with similar aryl-fused 5-membered dinitrogen
ring systems, such as 2,3-dihydrobenzo[d ]imidazoles, have
also been shown to be very effective organic hydride
donors.30,31 There are many examples for the application
of these hydride donors as reducing reagents for use in
organic synthesis.32-35 These systems are capable of redu-
cing many functional groups such as aldehydes, ketones,
olefins, imides, and organic halides; however, since they are
all achiral they require the presence of a chiral catalyst to
perform desired asymmetric reductions. The intrinsic chira-
lity, high reducing power, and potential bioactivity of the
TIP heterocycles synthesized could therefore make them
the focus of multiple areas of ongoing research within the
chemical and biological communities. Recently, we utilized a
TIP-based moiety as a key component in the development of
a “lockable molecular switch” which exploited the pH-based
cyclization and ring-opening process which could then be
“locked” by a redox process.36 However, we were not
able to isolate the TIP-based moiety previously.36 Herein we
show how we were able to develop the TIP chemis-
try to isolate a range of TIP-based compounds, and we
report an attractively simple procedure for their synthesis
along with a discussion of the mechanism and scope of the
reaction.
The TIP framework (Scheme 1, structure 3) is in fact an
intermediate in a multistep reaction between a primary amine
and 5-(2-bromoethyl)phenanthridinium bromide (BEP, 2)
to produce a cationic 2,3-dihydro-1H-imidazo[1,2-f]phenan-
thridinium heterocycle (DIP, 4).37,38 Compounds incorporat-
ing the DIP framework are an important class of heterocycles
in their own right and have been the focus of recent biological
studies due to their potent and unusual activity in ovarian
cancer cell lines.39-41 The mechanism for the synthesis of
DIPs involves three key steps; R addition of the amine to the
iminium moiety, a 5-exo-tet cyclization, and an oxidation via
“hydride loss” (Scheme 1).
The TIP intermediate is formed between steps two and
three of the mechanism so in order to isolate the TIP
intermediate the reaction conditions had to be optimized to
allow R addition and cyclization yet prevent further oxi-
dation. The initial monophasic procedure reported for
the synthesis of DIPs38 required 2 equiv of BEP starting
material per mole of primary amine, as 1 equiv combined
with the amine to generate the TIP intermediate and the
second 1 equiv was consumed as the stoichiometric oxidant
via a hydride transfer in the final oxidation step. A more
efficient biphasic procedure was subsequently developed to
maximize the reaction yield with respect to both reactants.38
This procedure utilizes phase transfer to separate the TIP
intermediate from the incompatible BEP starting material
and generates the TIP intermediate quantitatively. This
method is, however, limited to hydrophilic primary amines
only as the R addition step must occur in the aqueous phase
and the TIP structures generated from these aliphatic amines
have as yet only been characterized in situ by MS and NMR
spectroscopy.36,38 Isolation has proven to be difficult, and
attempts to isolate these compounds via solvent evaporation,
precipitation, and crystallization have all been unsuccessful.
The lack of success with respect to isolating TIP structures of
this nature has been attributed to their high reactivity toward
acidic and oxidative conditions and the constraints this
places on product isolation and purification; these issues
and other problematic side reactions are discussed in the
subsequent sections. In order to isolate the TIP intermediate,
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Richmond et al.
SCHEME 2. Inhibition of TIP Oxidation via Conjugation
JOCArticle
it was therefore necessary to develop a methodology that
could either (i) provide a suitable technique for the isolation
of TIPs generated from hydrophilic primary amine sub-
strates via the biphasic methodology or (ii) accommodate
hydrophobic amine substrates that would lead to the gene-
ration of TIP structures that were compatible with the
oxidative phenanthridinium framework of the BEP starting
material. The effects of solvent, steric bulk, and electronic
character of the primary amine side-chain were investigated,
and all were found to contribute significantly to the outcome
of the reaction.
Results and Discussion
The key parameters investigated were alteration of the
amine substrate and alteration of the solvent system. The
first issue to be tackled was that of solvent choice. The
solvent was required to be nonprotic to prevent pseudo-
base formation of the BEP under the basic conditions yet
remain polar enough to solvate the cationic species. DMF
and DMSO were the natural solvents of choice, and initial
assays carried out in deuterated solvents and analyzed in situ
by 1H NMR spectroscopy showed promising results. How-
ever, it was thought that due to their high boiling points and
miscibility with water isolation of the sensitive product
would be problematic. Chloroform was subsequently estab-
lished as the solvent of choice as it overcame the previous
issues of product isolation and was still able to solvate the
reactants, although somewhat sparingly with respect to BEP.
This, however, proved to be an advantageous trait as it
created a visual aid for monitoring the reaction process:
The BEP starting material is largely insoluble in chloroform,
but the products are completely soluble so as the reactants
are consumed the reaction mixture gradually evolves from
an off-white suspension to a bright orange solution, thus
indicating when the reaction has reached completion. The
mother liquor can then be washed with water to remove the
salt byproduct followed by low temperature evaporation of
solvent and excess organic base under vacuum to isolate the
TIP product. A range of amines were investigated and a
number of products containing the desired TIP framework
were isolated using this general methodology (Table 1, for
detailed methods and spectra see the Experimental Section
and ESD).
AEP core has formed it can also act as a “hydride acceptor”,
in a similar fashion to BEP, leading to further oxidation and
complete consumption of the TIP intermediate (Scheme 3,
step 2).
This concept was addressed in previous work where we
used a biphasic solvent system to overcome this undesired
side reaction for operation of a solution-based switchable
organic system.36 As the incompatible TIP and AEP forms 3
and 5 exist in equilibrium it is easy to see why the relative
stability of the aliphatic-TIP analogues is so low, especially
in monophasic solutions: The position of the equilibrium will
tend to favor one form over the other depending on the
availability of protons in solution, and the probability of a
successful collision and subsequent hydride transfer between
the two forms will be dependent upon concentration. How-
ever, over time, the two forms will irreversibly react and
ultimately lead to the consumption of TIP. This complicated
series of reactions was confirmed by monitoring the acid-
ification of a solution of TIP 3b in DMSO-d6 with DCl by 1H
NMR spectroscopy. From the spectra in Figure 1 it can
From the list of amine substrates investigated it can be
seen that there is a correlation between the availability of the
amino N lone pair and reaction success. It was hypothesized
that the susceptibility of the TIP structure to acidic and
oxidative conditions could be controlled by the degree of
conjugation of the N lone pair, which can be easily tuned by
judicious selection of the side chain. Higher degrees of
conjugation with the side chain will decrease the ability of
the lone pair to stabilize the positive charge in the DIP
product, thus reducing the driving force for the oxidation.
Scheme 2 shows the resonance representations of TIP and
DIP structures 3 and 4 with nonconjugating side chain R1
and conjugating side chain R2.
FIGURE 1. TIP 3b consumption via protonation and subsequent
hydride transfer: Structure and assigned peaks for DIP 4b in blue;
structure and assigned peaks for AEDP 6b in red. This figure shows
the general process that results in the conversion of the reactive TIP,
(top) TIP 3b, and excess isobutylamine before DCl addition and
(bottom) equimolar amounts of DIP 2 (blue) and AEDP 4b (red)
and excess isobutylamine hydrochloride after DCl addition, as we
have previously reported; see ref 36. In this work we were able to
tune the reaction methodology so that the TIP compounds could be
isolated; see Table 1.
Conjugation will also decrease the pKa of the nitrogen
center, making it less susceptible to protonation and subse-
quent generation of 5-(2-aminoethyl)phenanthridinium
(AEP) adducts 5 via ring-opening (Scheme 3, step 1). Pre-
venting this process is equally as important since once the
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TABLE 1. TIP Products Obtained via Reaction of Primary Amines with BEPa
aBEP (1.0 equiv), RNH2 (1.0 equiv), TEA (3.0 equiv), CHCl3, rt. bpKa values calculated using Advanced Chemistry Development (ACD/
Laboratories) Software V8.14 for Solaris (1994-2009 ACD/Laboratories). cIsolated product yield after normal workup. d5.0 equiv of TEA. Biphasic
reaction conditions can overcome the hydride transfer to provide short-lived solutions able to be characterized by MS and NMR spectroscopy (ESD).
eNo TIP formed due to steric hindrance. fNo TIP formed due to reduced amine nucleophilicity. g5.0 equiv of TEA.
AEP þ Hþþ 2e- f AEDPE ¼ ∼ -0:6V
ð2Þ
be seen that the solution of TIP 3b and isobutylamine (acting
as excess base) is converted to an equimolar mixture of
DIP 4b and AEDP 6b by addition of submolar equivalents
of DCl.
The resulting electronic potential for the cell is therefore
calculated as approximately þ0.7 V, which would result in a
highly negative value for ΔG° and a spontaneous redox
reaction under standard conditions.
The results for the selection of amines investigated
in Table 1 clearly demonstrate a dependency upon the
electron-withdrawing capacity of the R group for inhibition
of the oxidation step. Entries a-e in Table 1 showed no
observation of the corresponding TIP products after work-
up, which demonstrates that a lack of conjugation from the
aliphatic side chain increases the reactivity of the TIP with
respect to oxidation and protonation. This was verified by
The thermodynamic driving forces for this reaction are
likely to arise from the reduction of steric strain and
increased delocalization of the positive charge in the DIP/
AEDP products 4 and 6 compared to the TIP/AEP reactants
3 and 5. This is corroborated by consideration of the
standard electronic potential of the cell. Equations 1 and 2
show the electron half-equations and reduction potentials
for the reacting species (CV data in ESD).
DIP þ Hþ þ 2e- f TIPE ¼ ∼ -1:3V
ð1Þ
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SCHEME 3. Intermolecular TIP-AEP Hydride Transfera
aKey: (a) protonation and ring-opening of TIP to form AEP hydride acceptor and contrasting reverse reaction; (b) hydride transfer between TIP and
AEP to form the oxidation product, DIP, and the reduction product, 5-(2-aminoethyl)-5,6-dihydrophenanthridine (AEDP).
the presence of the oxidation product, DIP, in the product
mixture. In contrast, arylamines of varying electron defi-
ciency can be reacted with the BEP starting material to
generate the corresponding TIP structures in moderate to
excellent yields (Table 1, entries g-u). Partial conjugation of
the N lone pair to the π-system of the aromatic ring reduces
the potential for “hydride transfer” from the TIP intermedi-
ate to the BEP starting material, allowing complete conver-
sion of the BEP to the TIP product. Direct conjugation of the
N lone pair to the side chain in the form of an amide or
conjugation to a highly electron-deficient aromatic system
did not lead to production of any of the corresponding TIP
structures (Table 1, entries v-x). This can be explained by
the loss of sufficient nucleophilicity. In these cases, the
majority of the BEP starting material is recovered by filtra-
tion; however, the presence of phenanthridine in the filtrate
indicated conversion of some of the material via an elimina-
tion reaction.
reaction outcome cannot be formed here as the steric effects
of the amine side chains must also be considered.
The reduction potentials of a selection of DIP analogues
4a,b,i,j,t containing a mixture of aryl and aliphatic side
chains were measured to corroborate the influence of the
side chain on the electronic potential of the DIP framework
(Figure 3).
FIGURE 3. CV diagrams of compounds: 4a, R = cyclohexyl; 4b,
R = isobutyl; 4i, R = 3,4-dimethoxyphenyl; 4j, R = phenyl; 4t,
R = 3,4-difluorophenyl; at 100 mV/s. A decrease in reduction
potential with decreasing electron-withdrawing effect is observed.
From the plot, it can be seen that the values for the
reduction potentials decrease with the decreasing electron-
withdrawing character of the R groups. This supports the
hypothesis that the amine N lone pair is involved in stabilizing
the positively charged DIP core and that alteration of the R
group has a direct influence on this. This data, however, does
not allow for the electronic effects to be considered as the sole
contributing factor for stabilization of the TIP structure
under the standard reaction conditions as the reduction
potentials for the aryl-DIPs are still highly negative, >-1.0
V. This would theoretically still result in a spontaneous
hydride transfer between the aryl TIPs and phenanthridinium
based reactants 2 or 5. This reaction is possible, and there is
precedence for the synthesis of aryl DIPs from TIPs using
BEP as the oxidant.38 The effect of using an arylamine on the
reaction outcome must therefore be kinetic rather than
thermodynamic: The rate of the hydride transfer reaction
simply becomes relatively slower than amine addition and
FIGURE 2. TIP product yield vs amine pKa. Circled data point for
adamantyl-TIP 3f.
In terms of electronic effects, isolation of TIP structures
can be seen as a balancing act between having enough
nucleophilicity for the primary amine to undergo the first
two steps while retaining enough electron-withdrawing ca-
pacity to prevent further oxidation. It is proposed that the
pKa value of the primary amine substrate would be a quick
and simple measurement that could be useful in predicting
the reaction outcome. From the plot in Figure 2 it can be seen
that a window for successful TIP isolation can be estimated
for amines with pKa values of between approximately 2 and
7. It is notable that a direct correlation between pKa and
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JOCArticle
Bulkier amino substituents must protect this face of the
TIP structure by blocking the approach of the oxida-
tive phenanthridinium cations and inhibit the undesired
hydride transfer process. This was confirmed by studying
the reactions of isobutyl and adamantyl TIPs 3b and 3f with
BEP in DMSO-d6: In the former case the reaction resulted
in almost instant conversion of TIP 3b to DIP 4b, whereas
in the latter case both TIP 3f and BEP reactants were visible
in the reaction mixture even after 9 h (1H NMR spectra
in ESD).
Conclusions
In summary, we have developed a general methodology
for the synthesis and isolation of a number of heterocyclic
compounds containing a 1,2,3,12b-tetrahydroimidazo[1,2-f]-
phenanthridine framework. Compounds of this struc-
ture type will have interesting interactions with biological
systems. Our preliminary studies show the TIPs to have
comparable cytotoxicity levels to DIPs, and they are also
likely to show activity against certain bacteria, fungi, and
other biological targets.24-29 The high reducing power of the
chiral TIP framework coupled with their facile tunability also
make them interesting targets for the development of organic
reducing agents. The initial synthetic methodology developed
is unquestionably limited to aryl primary amines however our
investigations and demonstration of understanding of the
reaction processes will enable us to modify our procedures
to accommodate other primary amines and enhance the scope
of the methodology. Our future work will look toward
functionalizing the phenanthridine ring and the subsequent
effects on the stability of the TIP frameworks generated and
also toward application of the methodology for functionaliz-
ing aromatic systems other than phenanthridines, such as
quinolines, quinazolines, and pteridines to generate other new
heterocycles. We then aim to investigate the chemical and
biological applications of these compounds as well as the TIPs
in the areas discussed.
FIGURE 4. X-ray crystal structure of 3n.
cyclization, thus favoring TIP production. Electronic effects
from the amine substituents could contribute to lowering the
rate of hydride transfer relative to R addition and cyclization
but are unlikely to be solely responsible. Other effects such as
sterics must also be considered.
It was found that steric effects are indeed highly influential
on the reaction outcome and have an effect at each stage of
the multistep mechanism. From the series of successfully
isolated TIP structures 3f-u, a set of structural isomers were
selected to compare these effects. From the comparison of
electronically similar isomeric pairs (Table 1, entries k-r) it
can be seen that aryl substrates functionalized with bulky
substituents at the ortho positions are unable to form the TIP
products unlike those that are either meta or para substi-
tuted. The only ortho-functionalized substrate able to under-
go conversion to the TIP product 3m was 2-fluoroaniline 1m,
where the fluorine atoms relatively small steric bulk is not
sufficient to hinder the addition and cyclization steps. Ob-
serving the reactions in DMSO-d6 for 2- and 4-bromoaniline
1q and 1r showed that the BEP starting material was con-
sumed but no signals correlating to the TIP intermediate 3q
were observed after 2 h for the reaction of 2-bromoaniline 1q,
compared to the reaction of 4-bromoaniline 1r which had
reached complete conversion to TIP 3r after <15 min. The
1H NMR spectra of the 2-bromoaniline reaction showed
signals correlating to the amine starting material and also
phenanthridine free base indicating that in these cases the
highly reactive BEP starting material undergoes an elimina-
tion reaction rather than the desired addition and cyclization
(1H NMR spectra in ESD).
The isolation of the TIP analogue of adamantamine 3f was
a very important discovery as this highlighted the stabiliza-
tion of the TIP structure primarily through steric effects
rather than electronic inhibition. The amine substrate is a
nonconjugated aliphatic amine with a relatively high pKa
value of 10.75. With no conjugation of the amino N lone pair
with the adamantyl group it can be assumed that this
compound will have a similar electronic potential to other
aliphatic TIP analogues. The inhibition of the hydride
transfer and subsequent TIP stabilization must therefore
be influenced by the steric bulk of the amino side chain
alone. The crystal structure of 1-(4-fluorophenyl)-TIP 3n
shows the phenyl side chain deflecting out of the plane of the
TIP ring system on the same face as the R hydrogen
(Figure 4.)
Experimental Section
5-(2-Bromoethyl)phenanthridinium Bromide (2). Synthesized
following procedure reported by Parenty et al.:38 mp 235-236
1
°C dec; H NMR (DMSO, 400 MHz) δ 10.43 (s, 1H), 9.26 (d,
1H, J = 8.0 Hz), 9.21 (d, 1H, J = 8.0 Hz), 8.71 (d, 1H, J = 8.0
Hz), 8.68 (d, 1H, J = 8.0 Hz), 8.48 (t, 1H, J = 8.0 Hz), 8.18 (m,
3H), 5.57 (t, 2H, J = 6.0 Hz), 4.24 (t, 2H, J = 6.0 Hz); 13C NMR
(DMSO, 100 MHz) δ 156.5 (CH), 138.7 (CH), 134.7 (C), 133.1
(CH), 132.7 (C), 132.3 (CH), 130.7 (CH), 130.5 (CH), 125.8 (C),
125.2 (CH), 123.4 (CH), 123.1 (C), 119.9 (CH), 58.1 (CH2),
30.6 (CH2).
General Method for Synthesis of TIPs (3). To a stirred
suspension of BEP 2 (700 mg, 1.91 mmol, 1.0 equiv) in CHCl3
(50 mL) were added primary amine 1a-x (1.91 mmol, 1.0 equiv)
and TEA (798 μL, 5.73 mmol, 3.0 equiv). The resultant suspen-
sion was stirred under a nitrogen atmosphere until a solution
formed (0.5-18 h depending on the amine). The reaction
mixture was transferred to a separating funnel and washed with
water (2 ꢀ 20 mL) and brine (1 ꢀ 20 mL). The organic phase was
then dried over MgSO4 and the solvent was removed under
vacuum to give the crude TIP product, usually a pale colored
powder. In some cases, an optional methanol trituration was
used to improve the purity or to vitrify crude products that
formed oils rather than powders. Full experimental details and
characterization data for all compounds and intermediates
J. Org. Chem. Vol. 74, No. 21, 2009 8201

Richmond et al.
JOCArticle
are available in ESD. An example for compound 3g is shown
below.
1372 (m), 1337 (m), 1297 (s), 1210 (m), 809 (m), 749 (s), 734 (m);
MS (FAB) m/z 342.4 (M þ H)þ (100), 206.6 (10), 193.7 (37),
180.8 (23), 136.3 (25); HRMS (FAB) calcd for (C23H24N3)þ
342.1970, found 342.1965.
1-(4-Dimethylaminophenyl)-1,2,3,12b-tetrahydroimidazo[1,2-
f]phenanthridine (3g). General TIP synthesis method. Product
isolated as a pale grey powder (574 mg, 1.68 mmol, 88.1%): mp
197-199 °C (Et2O); 1H NMR (CDCl3, 400 MHz) δ 7.89 (d, 1H,
J = 7.8 Hz), 7.79 (d, 1H, J = 7.8 Hz), 7.42 (t, 1H, J = 7.8 Hz),
7.34 (t, 1H, J = 7.8 Hz), 7.26 (m, 2H), 7.04 (t, 1H, J = 7.8 Hz),
6.83 (m, 3H), 6.77 (m, 2H), 5.30 (s, 1H), 4.15 (m, 1H), 3.80 (m,
1H), 3.68 (m, 1H), 3.37 (m, 1H), 2.91 (s, 6H); 13C NMR (CDCl3,
100 MHz) δ 144.4 (C), 143.7 (C), 141.4 (C), 134.6 (C), 131.9 (C),
129.1 (CH), 127.7 (CH), 127.2 (CH), 124.6 (CH), 124.2 (C),
123.7 (CH), 123.3 (CH), 119.7 (CH), 115.6 (2 ꢀ CH2), 115.0 (2 ꢀ
CH2), 112.8 (CH), 75.6 (CH), 52.1 (CH2), 44.8 (CH2), 41.9 (2 ꢀ
CH3); IR (KBr, cm-1) 3433 (w), 3045 (w), 2927 (w), 2870 (w),
2841 (w), 2787 (w), 1597 (m), 1514 (s), 1493 (m), 1442 (m),
Acknowledgment. This work was supported by The
University of Glasgow and the EPSRC. We also thank
Dr. Yu-Fei Song for the crystallographic data and
Dr. Haralampos Miras for the CV measurements.
Supporting Information Available: Details of instruments
and materials, extended Experimental Section, CV data, NMR
spectra of products and intermediates, and crystallographic
data (CIF). This material is available free of charge via the
Internet at http://pubs.acs.org.
8202 J. Org. Chem. Vol. 74, No. 21, 2009