Discovery of an imidazo-phenanthridine synthon produced in a 'five-step one-pot reaction' leading to a new family of heterocycles with novel physical properties

Article abstract of DOI:10.1039/b517117b

A new class of heterocyclic aromatic cation with novel physical properties has been constructed by an unprecedented reaction pathway that proceeds via five spontaneous steps to yield a 'synthon' that can be further derivatised by a final nucleophilic subs

Full text of DOI:10.1039/b517117b

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Discovery of an imidazo-phenanthridine synthon produced in a ‘five-step
one-pot reaction’ leading to a new family of heterocycles with novel
physical properties{
Alexis D. C. Parenty, Kevin M. Guthrie, Yu-Fei Song, Louise V. Smith, Eric Burkholder and Leroy Cronin*
Received (in Cambridge, UK) 2nd December 2005, Accepted 3rd January 2006
First published as an Advance Article on the web 19th January 2006
DOI: 10.1039/b517117b
A new class of heterocyclic aromatic cation with novel physical
properties has been constructed by an unprecedented reaction
pathway that proceeds via five spontaneous steps to yield a
properties of the DIP framework are likely to come from
1
7
upstream DNA intercalation, the development of a metho-
dology leading to a more planar Imidazo-Phenanthridinium
framework (IP; Fig. 2) was very appealing since, not only will it
lead to a new family of imidazole-containing molecules, but also
potentially bind more strongly to DNA due to more favourable
p–p interactions. Moreover, the introduction of the imidazole
moiety would open up new possibilities for tuning the DNA
‘synthon’ that can be further derivatised by a final nucleophilic
substitution step.
Explorations in heterocyclic chemistry are exciting because of the
potential of discovering an almost unlimited resource of novel
compounds with diverse physical, chemical, and biological
intercalating platform, notably via substitution at C and C
1 2
1
18
properties. Heteroaromatic templates are therefore commonly
(Fig. 2), which is harder to modify in the case of DIPs. Herein,
we report a simple and efficient procedure leading to IPs from
an imidazole-based intermediate obtained in an unprecedented
five-step one-pot reaction.
used in medicinal chemistry for the design of biologically active
2
agents. In this respect, the imidazole framework is a particularly
3–5
important subset, widely implicated in biochemical processes.
This procedure builds upon our previous work, in which we
demonstrated that the formation of the DIP derivatives occurs via
addition of a primary amine to the highly reactive iminium moiety
of starting material 2-bromoethyl-phenanthridinium bromide 1,
followed by a five-membered ring cyclisation and an oxidation step
Indeed, the imidazolyl moiety is ubiquitous in many biologically
active compounds, and has a rich chemistry which makes it an
4,6
interesting building block in drug discovery. Furthermore, due
7
to the possible formation of stable N-heterocyclic carbenes, the
imidazole moiety has found wide-ranging applications in organo-
16,19
8
9
metallic catalysis, coordination chemistry and asymmetric
(Scheme 1).
1
0
catalysis. It is not surprising that an ever increasing amount of
research has focused on the improvement of the preparation and
functionalisation of the imidazole moiety, notably for its fusion
11–14
onto pre-existing N-heteroaromatic systems.
However, all
previously reported synthetic routes require the alpha position of
the N-heterocycle to be functionalised at some point by an amino-
based group (Fig. 1), which is often difficult to achieve as it
requires harsh reaction conditions, such as those found in the
Chichibabin reaction, or regio-selective halogenation followed by
15
nucleophilic substitution with ammonia.
Recently, we have developed a one-pot reaction leading
to Dihydro-Imidazo-Phenanthridinium derivatives (DIPs;
1
6
Scheme 1), a new class of heteroaromatic compound with
1
high cytotoxicity in cancer cell lines. As the biological
7
Scheme 1 Reported mechanism for the formation of DIPs. Reaction
conditions: a) H O/EtAc, NaHCO , 0 uC to r.t., N , 2 h; b) aqueous wash,
NBS, 0 uC to r.t., 2 h.
2
3
2
Fig. 1 A retro-synthetic approach for fused imidazole moieties.
WestCHEM, University of Glasgow, Department of Chemistry,
Glasgow, UK G12 8QQ. E-mail: L.Cronin@chem.gla.ac.uk
{ Electronic supplementary information (ESI) available: Full synthetic
and analytical details. See DOI: 10.1039/b517117b
Fig. 2 Representations of the DIP and IP framework.
1
194 | Chem. Commun., 2006, 1194–1196
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Table 1 Products and yields
IP #
Yield (%)
7
7
7
7
7
7
7
a
b
c
d
e
f
R = –H; X = Br
3
R = –(CH –CH ; X = Br
85
83
90
98
81
95
99
2
)
R = –benzyl; X = Br
3
R = p-methoxy-benzyl; X = Br
R = –benzyl; X = Cl
R = –CH
R = –CH
3
; X = I
g
3
; X = tosylate
dictated by the choice of the leaving groups used in the last
nucleophilic substitution step (Scheme 2). This is useful from the
drug discovery point of view since it is possible to produce a diverse
library of water-soluble compounds, by judicious choice of the
electrophilic reagent (See 7c and 7e,or7f and 7g). The presence of the
intermediate 3, 5 and 6 (see supplementary information) was
confirmed using mass spectrometry, and is in accordance with the
proposed mechanism shown in Scheme 2. The crystal structure of
compound 6 provides definitive proof for the formation of the
imidazole moiety (Fig. 3). Furthermore, the imidazo derivative 6was
obtained as a light yellow powder, which turned to blue in solution
after being left in the presence of sunlight for over 12 hours, which
Scheme 2 Synthesis of platform molecule imidazo-phenanthridine 6,
and imidazo-phenanthridiniums 7a–g (IPs).
The oxidation step which occurs during the final step of the
synthesis of the DIP molecules occurs readily due to the high
driving force which originates from the re-aromatisation of the
central ring (Scheme 1). Subsequent oxidation could not transform
the DIPs into the corresponding targeted IPs (Fig. 2) by using
conventional oxidizing agents,{ probably due to the high stability
20
might be caused by the presence of a stable radical species. Detailed
study of this photochromic process (which is not shown by the DIP
family of molecules) is underway. Structural analysis of 6§
demonstrates unambiguously the delocalised nature of the formal
1
of the fully aromatic DIP ring. However, the use of ammonia as a
nucleophile means that this aromaticity can be removed simply by
deprotonation giving a route to form the imidazole ring from a less
stable intermediate, see Scheme 2.
–
CLC– moiety into the five-membered ring and into the central
aromatic core (C–C and C–N bond lengths in the five-membered
17
˚
ring range from 1.360–1.385 A in IP cf. 1.331–1.521 A in DIP).
˚
Herein we show that when the starting material, 2-bromoethyl-
phenanthridinium bromide 1, is reacted with liquid ammonia it then
forms alpha adduct 2 which subsequently forms the imidazolidine
intermediate 3 via an intramolecular cyclisation (Scheme 2).
Addition of an excess of manganese dioxide under basic reaction
conditions gives rise to the two necessary oxidation steps required to
obtain the imidazo-phenanthridine intermediate 6 in quantitative
yield. This possibly proceeds via the formation of the acidic dihydro-
…
Also, compound 6 can be seen to aggregate via a range of C–H
p
and p–p interactions in the solid state, see Fig. 3. Therefore, this
additional planarity and extended electron delocalisation should
give rise to an improvement in the DNA binding affinity of IP vs.
DIP, and this indeed was observed, see Table 2.
To evaluate the DNA binding affinity of the IP framework, ITC
experiments were carried out in a PIPES buffer of 7b–d. Binding
4
5
21
constants in the region of 10 –10 M have been observed, which
are higher than the corresponding DIP analogues (Table 2).
In conclusion, we have developed an unprecedented one-pot
reaction yielding a key intermediate imidazo-phenanthridine
16
imidazo-phenanthridinium intermediate 4, which is deprotonated
in-situ to form the dihydro-imidazo-phenanthridine intermediate 5.
As a result, the migration of the iminium double bond during the
deprotonation of4removes thearomaticity of the phenanthridinium
moiety and provides a high driving force for the re-aromatisation
and transformation of the dihydro-imidazole moiety of 5 into the
imidazole moiety present in 6.
(
compound 6) simply and efficiently, using only a filtration
Subsequent nucleophilic substitution of a range of electrophiles
RX by the imidazo-phenanthridine 6 gives rise to a family of IP
derivatives 7a–g with high yield (Scheme 2 and Table 1). The last
step is particularly effective as it proceeds concurrently with
increased aromaticity. Precipitation of the cationic products 7a–g
from toluene during the reaction allows simple recovery by
filtration. Therefore, a large excess of the electrophilic reagent can
be used to drive the reaction to completion as the remaining
unreacted material stays in solution.
Fig. 3 LHS: ORTEP representation (30% probability ellipsoids) of the
molecular structure of the synthon imidazo-phenanthridine 6. RHS:
…
Note that the nature of the counter-ion formed during the
synthesis of the IP derivatives 7a–g (Scheme 2 and Table 1) is
Packed array of 6 showing p p stacking in the solid state.
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Table 2 DNA affinity of DIP (LHS) versus the corresponding IP structure (RHS)
a
21
4
a
21
4
DIP structure
Binding constants ; K (M ) 6 10
Corresponding IP structure
Binding constants ; K (M ) 6 10
3
4
2
.50 ¡ 0.14
.50 ¡ 0.15
.90 ¡ 0.11
5.28 ¡ 0.19
6.11 ¡ 0.40
11.8 ¡ 0.10
a
Salmon testes DNA.
610 nm appear. CCDC 289915. For crystallographic data in CIF or other
electronic format see DOI: 10.1039/b517117b
procedure to obtain the analytically pure product. This provides a
new route for the flexible synthesis of a new class of heterocycles
with novel physical properties arising from the increased planarity
and electron delocalisation over the entire heterocyclic framework.
The improved planarity can be shown by the DNA binding
affinity, compared to our Dihydro-Imidazo-Phenanthridinium
1
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derivatives (DIPs). The application of this one-pot reaction to
other N-heteroaromatic systems is presently under investigation, as
well as the development of an IP-library, with a particular view to
examine chiral and phase transfer systems. In addition, electro-
chemical and photolysis studies are underway to examine the
possibility of using DIP and IP to generate stable radical species.
This work was supported by the EPSRC and The University of
Glasgow.
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Notes and references
1
3
{
In an attempt to oxidize DIPs to IPs (Fig. 2), oxidizing agents such as
MnO , KMnO , DDQ, H , H SO and HNO had been tried with a
range of different solvents at different temperatures, without success.
1
2
4
2
O
2
2
4
3
4
21
§
(
Crystallographic data 6: [C15
0.50 6 0.50 6 0.25 mm) was analyzed with a Bruker Nonius Advance
diffractometer equipped with an APEX II CCD detector using Mo-Ka
10 2
H N ], Mr = 218.25 g mol ; colourless rod
1
1
˚
Synthesis, Stanley Thornes, Cheltenham, 1998, ch. 5, pp. 72–119.
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1
radiation (l = 0.71073 A) at 100(2) K. Monoclinic, space group P2 (no. 4),
˚
a = 11.4915(11), b = 12.2167(12), c = 16.0434(15) A, b = 108.288(5)u, V =
3
23
21
˚
2138.5(4) A , Z = 8, rcalcd = 1.356 g cm , m(MoKa) = 0.0082 cm
,
1
7 A. D. C. Parenty, L. V. Smith, K. M. Guthrie, D. L. Long, J. Plumb,
F(000) = 912, 11890 reflections measured, 5441 are independent (Rint
0
=
.0299) which were used in all calculations, 613 refined parameters and 1
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restraints, R1 = 0.0628, wR2 = 0.1106 (all data). Structure solution and
refinement were performed by using SHELTXL via APEX2 software
+
21
package. Characterization of 6: [MH] = 219 g mol ; UV-Vis (CHCl
2
3
3
):
55 nm (4.4 6 10 ), 300 nm (1.3 6 10 ), 352 nm (2130), 370 nm (1670) and
86 nm (sh). UV kinetic measurement of the deep blue solution shows
5
5
absorbance at 250 nm, 290 nm, 305 nm (sh), which are all shifted to high
energy. At the same time, two obvious absorption peaks at 565 nm and
20 Y. H. Zhou, W. E. Baker, P. M. Kazmaier and E. Buncel, Can.
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1
196 | Chem. Commun., 2006, 1194–1196
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