One-pot synthesis of dihydroimidazo- and imidazophenanthridinium salts

Article abstract of DOI:10.1055/s-2007-983895

Two highly efficient and general one-pot annulation reactions are described for the synthesis of dihydroimidazo- and imidazophenanthridinium salts (DIPs⁺ and IPs⁺). These two methodologies exploit the difference in reactivity between

Full text of DOI:10.1055/s-2007-983895

PRACTICAL SYNTHETIC PROCEDURES
155
One-Pot Synthesis of Dihydroimidazo- and Imidazophenanthridinium Salts
O
A
ne-Pot Synthesis
l
of
D
ih
e
ydroimidaz
x
o-
a
nd Imida
i
zophen
s
anthridinium Sa
D
lts . C. Parenty,* Leroy Cronin*
WestCHEM, University of Glasgow, Chemistry Department, Glasgow, G12 8QQ, UK
Fax +44(141)3304888; E-mail: alexisp@chem.gla.ac.uk; E-mail: l.cronin@chem.gla.ac.uk
Received 15 February 2007
PSP
No108
Abstract: Two highly efficient and general one-pot annulation reactions are described for the synthesis of dihydroimidazo- and imida-
zophenanthridinium salts (DIPs and IPs ). These two methodologies exploit the difference in reactivity between primary amino-based or
ammonia nucleophiles and the dielectrophilic starting material, 2-bromoethylphenanthridinium bromide.
+
+
Key words: annulation reaction, heterocycles, phenanthridinium derivatives, DNA intercalating agents, anticancer agents
Br
a
b
Br
Procedure 1
6
3-99%
N
N
N
N
Br
Br
1
4
a–h
+
NH
N
N
2
3
R
R
R
R
NH2
Reaction conditions:
a: H2O–EtOAc, Na2CO3, N2, r.t., 2 h
b: aqueous wash, NBS, r.t., 2 h in the dark
dihydroimidazophenanthridinium derivatives
DIP+)
(
R = aliphatic group or hydrogen
Br
b
a
Procedure 2
N
N
N
N
Br
Br
1
+
5
N
N
N
6
7
H
H
H
H
NH3
X
Reaction conditions:
a: liquid NH3, –78 °C, 1 h
b: Na2CO3, MnO2, –78 °C to reflux
in toluene, 3 h, filtration
c: R-X, toluene, overnight reflux
c
N
N
81–99%
N
100%
1
0a–e
N
N
N
8
9
R
R = aliphatic group or hydrogen
imidazophenanthridinium
derivatives (IP+)
+
+
Scheme 1 The ‘one-pot’ reaction methodologies leading to DIPs (Procedure 1) and IPs (Procedure 2)
Introduction
flexible synthetic procedures that could increase the struc-
tural complexity of a given target whilst decreasing the
Improvements in screening methods in the pharmaceuti- number of synthetic steps. Efficient syntheses leading to
cal industry have encouraged the development of highly N-heteroaromatic cations are particularly appealing be-
cause they often have high affinity for DNA as a result of
1
their planar structure and charged characteristics. In this
respect, molecules containing the phenanthridinium core
are an important subset of heteroaromatic cations as they
SYNTHESIS 2008, No. 1, pp 0155–0160
x
x
.
x
x
.2
0
0
7
Advanced online publication: 11.09.2007
DOI: 10.1055/s-2007-983895; Art ID: Z04007SS
Georg Thieme Verlag Stuttgart · New York
©

1
56
A. D. C. Parenty, L. Cronin
PRACTICAL SYNTHETIC PROCEDURES
2
+
+
have numerous applications as drugs, DNA targeting Table 1 Some DIP and IP Derivatives Obtained via Procedures
3
4
5
1, 1¢ and 2 (continued)
agents, dyes, and DNA probes. Recently, we have ex-
ploited the reactivity of the dielectrophile 2-bromoeth-
ylphenanthridinium in two annulation reactions that
produce two new cationic heterocyclic frameworks based
Entry Structure
Yield (%)/
Procedure
6
7
4d
63/1
on the dihydroimidazo- and imidazophenanthridinium
moieties. Both procedures have allowed the synthesis of a
library of phenanthridinium derivatives with a range of in-
teresting physical and chemical properties including resis-
Br
N
8
,9
7,9,10
tance to hydrolysis, excellent DNA affinity,
and
O
N
cytotoxicity on cancerous cell lines A2780, A2780/cp70,
9
,10b
H
and MCP1.
O
The dielectrophilic starting material 1 (Scheme 1), com-
mon in both procedures, is easily prepared by reacting
phenanthridine with an excess of 1,2-dibromoethane (see
experimental part). The reaction mechanisms of the fol-
lowing two procedures have been thoroughly studied and
a
4
e
73 /1¢
Br
6
,7,11
are now well understood:
In a water/ethyl acetate
N
+
biphasic system, the DIP synthesis (Procedure 1,
Scheme 1) is initiated by a nucleophilic addition of a pri-
mary amine at the iminium moiety of 1 leading to interme-
diate 2. The resulting secondary amine undertakes a rapid
five-membered ring cyclisation to give the imidazolidine
intermediate 3, which can be extracted in the organic lay-
er. Subsequent oxidation of intermediate 3 via addition of
N-bromosuccinimide (NBS) leads to the formation of di-
N
a
4
f
98 /1¢
Br
N
N
+
hydroimidazophenanthridinium bromide (DIP ) 4, which
precipitates from the solution and is recovered by filtra-
tion (Scheme 1 and Table 1).
N
N
Br
+
+
Table 1 Some DIP and IP Derivatives Obtained via Procedures
, 1¢ and 2
a
4
g
95 /1¢
1
Entry Structure
Yield (%)/
Procedure
Br
N
Br
N
N
N
4
4
a
96/1
N
Br
Br
N
N
N
N
HN
Br
b
91/1
a
4
h
91 /1¢
Br
N
N
N
4
c
99/1
N
N
N
Br
Br
N
N
Br
N
O
Synthesis 2008, No. 1, 155–160 © Thieme Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Dihydroimidazo- and Imidazophenanthridinium Salts
157
+
+
Table 1 Some DIP and IP Derivatives Obtained via Procedures
, 1¢ and 2 (continued)
after filtering off the residual inorganic reactants and side
1
products. The desired imidazophenanthridinium salts
+
(
IP ) 10a–e are obtained by reacting compound 9 with a
Entry Structure
Yield (%)/
Procedure
range of electrophiles, and recovered by filtration
Scheme 1 and Table 1).
(
1
0a
85/2
Br
Scope and Limitations
N
We have tested both Procedures 1 and 2 on N-heterocyclic
systems other than phenanthridine and have encountered
the following limitations: (1) None of the procedures are
applicable to pyridine as the reactions invariably leads to
ring-opening side reactions of the pyridine moiety upon
nucleophilic attack of the iminium moiety;12 (2) Proce-
dure 1 leads to a disproportionation reaction that halves
N
H
1
1
1
0b
0c
0d
99/2
95/2
98/2
O
S
O
N
N
N
O
the yield when applied to quinoline derivatives
N
N
N
6
(
Scheme 2); and (3) Procedure 2 also works on quinoline,
isoquinoline, quinazoline and phthalazine derivatives but
better results are obtained when a biphasic system (tolu-
ene/ammonia) is used in the first stage of the reaction: this
partitions intermediate 6 in the organic phase, away from
the ammonia phase containing starting material 1, there-
I
13
fore avoiding unwanted redox side-reactions.
Also, it is worth noting some limitations of Procedure 1
concerning the nature of the amines that can be used: (1)
Br
+
Polyamine derivatives, expected to lead to poly-DIP de-
rivatives with poly-DNA intercalation properties, could
not be obtained via Procedure 1 for solubility reasons.
This is because the corresponding intermediate 3, bearing
another amino-tail on its R group, is compartmented in the
organic layer of the biphasic system, away from another
equivalent of 1 that is necessary to perform a new reaction
cycle; and (2) Also, Procedure 1 is not effective with aro-
matic amines due to a side reaction originating from the
alpha addition of the more nucleophilic hydroxide ion
formed in the aqueous layer. Note that the limitations con-
cerning the nature of the amine can be overcome by
changing the reaction conditions (Procedure 1¢,
Scheme 3). In a monophasic system in a solution of DMF,
it is possible to use polyamines and aromatic amines as
long as two equivalents of 1 are present: one equivalent
used as an electrophile and another one as an oxidizing
agent.6
O
1
0e
81/2
Cl
N
N
a
Note that molecule 11, the reduced form of 1, stays in so-
lution while the final product DIP 4e–h is recovered after
Yield based on the consumption of amine.
+
precipitation by addition of diethyl ether (Scheme 3 and
Table 1). Using these modifications, DIP derivatives
+
The first three steps of the synthesis of IP derivatives are
+
+
identical to those of DIP discussed above: In liquid am-
monia, starting material 1 undertakes an a-addition to
form intermediate 5, followed by a cyclisation to form im-
functionalised with aromatic R groups could be obtained,
+
as well as really large architectures of Poly-DIP mole-
cules containing 3 to 16 units.
idazolidine intermediate 6 that is oxidised by MnO to the
2
acidic intermediate 7. Deprotonation of dihydroimidazoli-
um 7 takes place in the solution of ammonia, yielding the
intermediate dihydroimidazole 8. The final oxidation step
leading to imidazophenanthridine 9 occurs at higher tem-
perature after evaporation of ammonia and reflux in tolu-
ene. Compound 9 can be isolated in a quantitative yield in the published literature.
Procedures
In this paper, we report the detailed protocols for Procedures 1, 1¢
and 2, along with the analytical data for some DIP and IP deriva-
tives. The characterisation of the remaining molecules can be found
+
+
6
,7
Synthesis 2008, No. 1, 155–160 © Thieme Stuttgart · New York

1
58
A. D. C. Parenty, L. Cronin
PRACTICAL SYNTHETIC PROCEDURES
H H
H
H
H
N
R
R
N
N
1
/2
procedure 1
H
+
1
/2
+
N
R
N
Br
R
NH2
N
N
Scheme 2 Disproportionation issue when applying Procedure 1 to quinolinium-based heterocycles
a
N
N
N
H
4
e–h
N
N
1
+
R
R
Br
DIP+
3
R
NH2
7
3–98%*
Reaction conditions:
a: 2 equiv of 1, DMF, Et3N, N2, r.t., 48 h
R = aromatic group or
N
N
a linker between several DIP+ units
1
11
H H
Br
Br
Scheme 3 Procedure 1¢: Modification of Procedure 1 to accommodate the use of aromatic amines and polyamines; * yield based on the con-
sumption of amine
All starting materials and solvents were commercially available (re-
agent grade) and used as supplied, from Aldrich Chemical Co.,
(CH), 126.57 (C), 125.13 (CH), 123.32 (C), 123.00 (CH), 118.91
(CH), 58.87 (CH ), 29.41 (CH ).
2
2
1
13
without further purification. H NMR and C NMR were recorded
using a Bruker DPX 400 spectrometer operating at 400 and 100
MHz, respectively. Chemical shifts (d) are given in ppm relative to
residual solvent peak. Infra red spectral analyses were performed on
a JASCO 410 spectrophotometer using a KBr disc; peaks are quoted
MS (EI): m/z (%) = 288.1 (M – Br, 100), 206.2 (8).
Anal. Calcd for C H Br N: C, 49.32; H, 3.59; N, 3.84. Found: C,
15 13
2
4
9.15; H, 3.48; N, 3.76.
CAUTION: Product 1 was found to be an extreme irritant and al-
lergenic material. Appropriate safety protection and utmost care are
required while preparing and handling this compound.
–
1
in wave numbers (cm ) and their relative intensities are reported as
follows: s = strong, m = medium, w = weak. Mass spectra were ob-
tained using a JEOL JMS 700 spectrometer operating in FAB, EI,
or CI mode. Microanalyses were performed on a CE-440 elemental
analyser. Melting points were determined on a digital IA9000 series
melting point apparatus, using capillary tubes.
+
Procedure 1: Monomeric DIP Derivatives 4a–d from Aliphatic
Amines
To a biphasic solution of 5% aq Na CO (20 mL) and EtOAc (40
2
3
mL) was added the primary amine or its HCl salt (2.1 mmol) fol-
lowed by 2-bromoethylphenanthridinium bromide (1; 700 mg, 1.9
2
-Bromoethylphenanthridinium Bromide (1)
Phenanthridine (5.44 g, 30.4 mmol) was dissolved in 1,2-dibromo-
ethane (114.2 g, 52 mL, 608 mmol) and stirred at 100 °C for 5 d .
During that time, the precipitate that formed was filtered every day,
rinsed with 1,2-dibromoethane (5 mL), and the mother liquor was
returned to stir at 100 °C until the next filtration. The reaction was
complete when no more precipitate formed. The precipitates were
combined and washed thoroughly with acetone to give 1 (7.92g,
mmol). The mixture was stirred under N at r.t. for 2 h. The organic
2
layer was separated, washed with H O (2 × 40 mL) and placed in a
2
round-bottomed flask covered with aluminum foil. NBS (375 mg,
2
.1 mmol) was added to the stirred solution at 0 °C, and the mixture
left stirring at r.t. for 2 h in the dark. The precipitate was filtered and
+
washed with Et O to yield the corresponding DIP frameworks 4a–
2
d.
9
5%) as a beige powder; mp 234–235 °C (dec.).
IR (KBr): 2947 (w), 1620 (m), 763 (s), 717 cm–1 (m).
2,3-Dihydro-1H-imidazo[1,2-f]phenanthridin-4-yliumBromide
(
4a)
1
H NMR (D O, 400 MHz): d = 9.81 (s, 1 H), 8.72 (d, J = 7.2 Hz, 1
2
Yield: 550 mg (96%); yellow powder; mp 392–394 °C (dec.).
H), 8.63 (d, J = 7.2 Hz, 1 H), 8.37 (d, J = 7.2 Hz, 1 H), 8.26 (d,
J = 7.2 Hz, 1 H), 8.18 (t, J = 7.2 Hz, 1 H), 7.98 (t, J = 7.2 Hz, 1 H),
IR (KBr): 3435 (s), 3028 (m), 2997 (m), 2950 (m), 2773 (w), 2684
(
1
w), 2050 (w), 1626 (s), 1608 (s), 1585 (s), 1469 (m), 1454 (m),
358 (m), 1294 (m), 1267 (w), 1169 (w), 1022 (w), 754 cm (s).
7
.90 (m, 2 H), 5.37 (t, J = 5.8 Hz, 2 H), 4.05 (t, J = 5.8 Hz, 2 H).
–
1
1
3
C NMR (D O, 100 MHz): d = 155.27 (CH), 139.03 (CH), 135.59
2
(
C), 133.18 (CH), 132.78 (C), 132.58 (CH), 130.85 (CH), 130.72
Synthesis 2008, No. 1, 155–160 © Thieme Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Dihydroimidazo- and Imidazophenanthridinium Salts
159
1
H NMR (D O, 400 MHz): d = 7.83 (d, J = 8.0 Hz, 1 H), 7.79 (d,
Anal. Calcd for C H BrN ·0.5H O: C, 65.30; H, 4.70; N, 7.25.
Found: C, 65.71; H, 4.53; N, 7.11.
2
21 17
2
2
J = 8.0 Hz, 1 H), 7.66 (t, J = 8.0 Hz, 1 H), 7.46 (m, 3 H), 7.28 (t,
J = 8.0 Hz, 1 H), 6.93 (d, J = 8.0 Hz, 1 H), 4.13 (t, J = 10.8 Hz, 2
H), 3.91 (t, J = 10.8 Hz, 2 H).
+
cis-1,3,5-Triaminocyclohexane DIP Polymeric Derivative 4h
1
3
Yield: 850 mg (91%); yellow powder; mp 360 °C.
C NMR (D O, 100 MHz): d = 154.69 (C), 135.75 (CH), 133.18
2
(
(
(
C), 131.65 (C), 129.56 (CH), 126.26 (CH), 125.65 (CH), 123.40
CH), 123.01 (CH), 119.25 (C), 115.45 (CH), 113.64 (C), 47.62
CH ), 43.04 (CH ).
IR (KBr): 3421 (s), 1610 (s), 1570 (s), 1533 (s), 1452 (m), 1386 (w),
1304 (s), 1263 (s), 1155 (m), 1122 (m), 783 (m), 754 (s), 717 (m),
669 cm (m).
–
1
2
2
1
MS (EI+): m/z (%) = 220 (M – Br, 10), 219.3 (12), 142.3 (8), 112.2
5), 100.2 (15), 86.2 (100), 56.1 (50).
H NMR (DMSO-d , 400 MHz): d = 9.11 (d, J = 8.4 Hz, 3 H), 8.91
6
(
(d, J = 8.4 Hz, 3 H), 8.73 (d, J = 8.0 Hz, 3 H), 8.18 (t, J = 5.1 Hz, 3
H), 8.04 (t, J = 5.1 Hz, 3 H), 7.86 (t, J = 5.1 Hz, 3 H), 7.70 (d,
J = 8.0 Hz, 3 H), 7.64 (t, J = 5.1 Hz, 3 H), 5.93 (m, 3 H), 4.79 (t,
J = 6.9 Hz, 6 H), 4.53 (t, J = 6.9 Hz, 6 H), 2.82 (q, J = 11.6 Hz, 3
H), 2.6 (d, J = 11.6 Hz, 3 H).
Anal. Calcd for C H BrN : C, 59.82; H, 4.35; N, 9.30. Found: C,
1
5
13
2
5
9.39; H, 4.23; N, 9.03.
1
-(4-Methoxybenzyl)-2,3-dihydro-1H-imidazo[1,2-f]phenan-
1
3
thridin-4-ylium Bromide (4c)
C NMR (DMSO-d , 100 MHz): d = 156.31 (CH), 135.53 (CH),
6
Yield: 792 mg (99%); off-white powder; mp 245–246 °C (dec.).
135.25 (C), 133.11 (CH), 131.82 (CH), 130.40 (CH), 129.17 (CH),
25.80 (C), 124.68 (CH), 124.23 (C), 120.41 (CH), 116.32 (C),
115.85 (CH), 52.66 (CH ), 46.25 (CH ), 45.54 (CH), 32.43 (CH ).
1
IR (KBr): 3431 (s), 2924 (w), 2360 (w), 1612 (s), 1576 (s), 1514
m), 1456 (m), 1304 (m), 1248 (m), 1026 (m), 814 (m), 754 cm–1
m).
2
2
2
(
(
1
MS (FAB): m/z (%) = 247.14 [(M – 3⋅Br)/3, 5), 232.1 (11), 219.11
(10), 214.08 (2), 157.1 (45), 79.7 (100).
H NMR (CDCl , 400 MHz): d = 8.52 (d, J = 8.2 Hz, 1 H), 8.36 (d,
3
J = 8.2 Hz, 1 H), 8.21 (d, J = 8.2 Hz, 1 H), 7.93 (t, , J = 8.2 Hz, 1
H), 7.69 (t, J = 8.2 Hz, 1 H), 7.56 (t, J = 8.2 Hz, 1 H), 7.51 (m, 2 H),
Anal. Calcd for C H Br N : C, 62.40; H, 4.62; N, 8.56. Found: C,
62.30; H, 4.71; N, 8.64.
5
1
45
3
6
7
5
.32 (d, J = 8.2 Hz, 2 H), 6.91 (d, J = 8.2 Hz, 2 H), 5.41 (s, 2 H),
.04 (t, J = 10.6 Hz, 2 H), 4.68 (t, , J = 10.6 Hz, 2 H), 3.76 (s, 3 H).
+
Procedure 2: IP Derivatives 10a–e
1
3
To a stirred solution of ammonia (50 mL) at –78 °C on a dry ice/
acetone bath was added 2-bromoethylphenanthridinium bromide
C NMR (CDCl , 100 MHz): d = 160.26 (C), 154.91 (C), 136.30
3
(
(
(
(
C), 135.79 (CH), 133.25 (C), 132.25 (CH), 129.49 (CH), 128.34
CH), 127.94 (CH), 126.28 (CH), 125.29 (C), 124.42 (CH), 123.96
CH), 120.93 (C), 116.38 (CH), 115.91 (C), 115.40 (CH), 55.81
CH ), 55.36 (CH ), 52.54 (CH ), 47.72 (CH ).
(
1; 700 mg; 1.9 mmol). The cooling bath was removed to allow the
mixture to warm up to –30 °C, the boiling point of ammonia, and
the reaction left stirring at that temperature for 1 h to yield the inter-
mediate 6. The reaction medium was returned to –78 °C before add-
ing under stirring Na CO (1 g, 9.4 mmol) followed by MnO (1.65
3
2
2
2
MS (FAB): m/z (%) = 341.2 (M – Br, 35), 232 (10), 157.1 (56),
21.2 (13), 79.7 (100).
2
3
2
1
g, 19 mmol), and the cooling bath was removed to allow the evapo-
ration of ammonia (1–2 h), yielding intermediate 8 along with inor-
ganic side products. The dry residue was suspended in toluene (20
mL) and refluxed for 3 h. The mixture was then filtered on glass frit
No. 4 and the residue rinsed extensively with acetone. Finally, the
mother liquor was concentrated to dryness to afford 9 (410 mg,
Anal. Calcd for C H BrN O·0.5H O: C, 64.19; H, 5.15; N, 6.51.
Found: C, 64.87; H, 5.47; N, 6.95.
23
21
2
2
+
+
Procedure 1¢: Polymeric DIP Derivatives or DIPs 4e–h
Derived from Aromatic Amines
To a solution of primary amine (0.95 mmol of amino group) and
quant.) as a light yellow powder; mp 77–78 °C; R = 0.3 (EtOAc).
f
Et N (530 mL, 3.8 mmol) in DMF (20 mL) was added 2-bromoeth-
3
9
ylphenanthridinium bromide (1; 700 mg, 1.9 mmol). After stirring
IR (KBr): 3432 (s), 1629 (m), 1532 (m), 1495 (w), 1463 (m), 1439
for 48 h at r.t. under N , the final product and the triethylamine hy-
2
–
1
(
m), 1316 (m), 1262 (s), 1104 (s), 803 (m), 719 cm (s).
drobromide were precipitated from the solution with Et O (100 mL)
2
and recovered by filtration. The precipitate was washed thoroughly
1
H NMR (CDCl , 400 MHz): d = 8.79 (m, 1 H), 8.51 (dd, J = 8.0,
3
with Et O and triturated with a small amount of H O (3 × 1 mL) to
2
2
1.0 Hz, 1 H), 8.42 (m, 1 H), 8.05 (d, J = 1.2 Hz, 1 H), 7.93 (dd,
J = 8.0, 1.0 Hz, 1 H), 7.7 (m, 3 H), 7.68 (d, J = 1.2 Hz, 1 H), 7.58
remove the triethylamine hydrobromide salt, yielding after drying,
+
the corresponding DIP derivatives 4e–h.
(
td, J = 8.0, 1.0 Hz, 1 H).
1
3
C NMR (CDCl , 100 MHz): d = 142.08 (C), 131.49 (C), 130.45
3
1
-Phenyl-2,3-dihydro-1H-imidazo[1,2-f]phenanthridin-4-yl-
(
(
(
C), 129.19 (CH), 129.06 (CH), 128.86 (CH), 127.68 (C), 125.53
CH), 124.59 (CH), 124.29 (CH), 122.42 (CH), 121.91 (C), 115.94
CH), 112.15 (CH).
ium Bromide (4e)
Yield: 260 mg (73%); yellow powder; mp 355–356 °C (dec.).
IR (KBr): 3434 (s), 3047 (w), 1612 (m), 1599 (m), 1575 (s), 1545
–
1
MS (FAB): m/z (%) = 219.4 (M + 1, 100), 178.7 (3), 164.9 (2), 98.8
5), 71.2 (7), 57.4 (10).
(
s), 1485 (w), 1440 (m), 1309 (s), 1171 (w), 935 (w), 758 cm (s).
(
1
H NMR (CD OD, 400 MHz): d = 8.85 (d, J = 8.4 Hz, 1 H), 8.75 (d,
3
Anal. Calcd for C H N : C, 82.55; H, 4.62; N, 12.84. Found: C,
8
1
5
10
2
J = 8.4 Hz, 1 H), 8.05 (t, J = 8.4 Hz, 1 H), 7.93 (t, J = 8.4 Hz, 1 H),
2.40; H, 4.65; N, 12.90.
7
.81 (d, J = 8.4 Hz, 1 H), 7.71 (m, 6 H), 7.45 (m, 2 H), 5.04 (t,
J = 10.4 Hz, 2 H), 4.69 (t, J = 10.4 Hz, 2 H).
Freshly made imidazophenanthridine 9 (410 mg, 1.9 mmol) was
1
3
dissolved in toluene (20 mL) and the electrophilic agent RX (2–20
C NMR (CD OD, 100 MHz): d = 154.87 (C), 144.05 (C), 141.02
3
14
equiv) was added. The reaction was stirred overnight under re-
(
(
1
1
CH), 137.69 (CH), 137.07 (CH), 134.63 (C), 133.20 (CH), 132.60
CH), 132.02 (CH), 129.94 (CH), 129.24 (CH), 128.47 (CH),
26.45 (CH), 125.76 (CH), 122.72 (C), 120.46 (C), 117.43 (CH),
17.00 (C), 56.19 (CH ), 48.76 (CH );
1
5
flux. The final product precipitates from the solution and is recov-
ered by filtration. The residue was washed extensively with diethyl
ether and dried to yield the corresponding imidazophenanthridini-
2
2
+
um framework IP 10a–g.
MS (FAB): m/z (%) = 297 (M – Br, 100), 269 (2), 230 (8), 219 (4),
78 (4), 154 (6), 136 (5), 107.2 (1), 77.6 (2).
1
Synthesis 2008, No. 1, 155–160 © Thieme Stuttgart · New York

1
60
A. D. C. Parenty, L. Cronin
PRACTICAL SYNTHETIC PROCEDURES
1
H-Imidazo[1,2-f]phenanthridinium Bromide (10a)
Anal. Calcd for C H BrN O: C, 65.88; H, 4.57; N, 6.68; 3.82.
Found: C, 65.96; H, 4.50; N, 6.53.
2
3
19
2
Yield: 483 mg (85%); white powder; mp 337–339 °C (dec.).
IR (KBr): 3030 (s), 2842 (s), 2669 (s), 1660 (w), 1628 (s), 1559 (s),
1
6
1
533 (m), 1469 (m), 1446 (m), 1395 (m), 915 (w), 757 (s), 716 (s),
Acknowledgment
91 (m), 611 cm–1 (w).
We thank the EPSRC, Scottish Enterprise, and the University of
Glasgow for their financial support.
H NMR (D O, 400 MHz): d = 7.57 (d, J = 2.0 Hz, 1 H), 7.33 (d,
2
J = 2.0 Hz, 1 H), 7.14 (m, 3 H), 7.07 (t, J = 7.4 Hz, 2 H), 6.97 (d,
J = 7.4 Hz, 2 H), 6.92 (t, J = 7.4 Hz, 1 H).
1
3
C NMR (D O, 100 MHz): d = 135.63 (C), 132.39 (CH), 130.34 References
2
(
(
(
CH), 129.24 (CH), 127.87 (CH), 127.09 (C), 126.57 (C), 122.85
CH), 122.41 (CH), 121.94 (CH), 120.66 (CH), 19.36 (C), 115.49
CH), 114.12 (CH), 113.21 (C).
(
1) Brana, M. F.; Cacho, M.; Gradillas, A.; de Pascual-Teresa,
B.; Ramos, A. Curr. Pharm. Des. 2001, 7, 1745.
(
2) (a) Morohashi, K.; Yoshino, A.; Yoshimori, A.; Saito, S.;
Tanuma, S.; Sakaguchi, K.; Sugawara, F. Biochem.
Pharmacol. 2005, 70, 37. (b) Boibessot, I.; Tettey, J. N. A.;
Skellern, G. G.; Watson, D. G.; Grant, M. H. J. Vet.
Pharmacol. Ther. 2006, 29, 547. (c) Harayama, T.;
Akiyama, T.; Nakano, Y.; Shibaike, K.; Akamatsu, H.; Hori,
A.; Abe, H.; Takeuchi, Y. Synthesis 2002, 237.
MS (FAB): m/z (%) = 219.4 (M – Br, 85), 188.6 (100), 187.6 (90),
5.8 (80), 78.0 (20), 59.3 (10), 48.4 (8).
9
Anal. Calcd for C H BrN ·2H O: C, 53.75; H, 3.51; N, 8.36.
Found: C, 53.60; H, 3.48; N, 8.36.
1
5
11
2
2
1
-Methyl-1H-imidazo[1,2-f]phenanthridinium Tosylate (10b)
Yield: 760 mg (99%); white powder; mp 115–116 °C.
(3) (a) Whittaker, J.; McFadyen, W. D.; Baguley, B. C.; Murray,
V. Anti-Cancer Drug Des. 2001, 16, 81. (b) Whittacher, J.;
McFadyen, W. D.; Wickham, G.; Wakelin, L. P. G.; Murray,
V. Nucleic Acids Res. 1998, 26, 3933.
IR (KBr): 3441 (m), 3113 (m), 3087 (m), 1706 (w), 1615 (w), 1561
(
1
m), 1532 (m), 1472 (w), 1357 (w), 1215 (s), 1198 (s), 1119 (s),
033 (s), 1010 (s), 817 (w), 755 (s), 680 (s), 567 cm (s).
–
1
(
4) Ihmels, H.; Otto, D. Top. Curr. Chem. 2005, 258, 161.
1
H NMR (D O, 400 MHz): d = 7.91 (d, J = 2.4 Hz, 1 H), 7.77 (d,
2
(5) (a) Pennadam, S. S.; Ellis, J. S.; Lavigne, M. D.; Górecki, D.
C.; Davies, M. C.; Alexander, C. Langmuir 2007, 23, 41.
(b) Sammes, P. G.; Shek, L.; Watmore, D. Chem. Commun.
J = 8.0 Hz, 1 H), 7.67 (d, J = 2.4 Hz, 1 H), 7.64 (d, J = 8.0 Hz, 1 H),
7
7
.55 (d, J = 8.0 Hz, 2 H), 7.45 (m, 3 H), 7.41 (t, J = 8.0 Hz, 1 H),
.32 (t, J = 8.0 Hz, 1 H), 7.29 (t, J = 8.0 Hz, 1 H), 7.23 (t, J = 8.0
2000, 1625.
Hz, 1 H), 7.11 (d, J = 8.0 Hz, 2 H), 3.90 (s, 3 H), 2.16 (s, 3 H).
(6) Parenty, A. D. C.; Smith, L. V.; Pickering, A. L.; Long, D.
1
3
L.; Cronin, L. J. Org. Chem. 2004, 69, 5934.
C NMR (D O, 100 MHz): d = 142.17 (C), 139.41 (C), 134.57 (C),
2
(
7) Parenty, A. D. C.; Guthrie, K. M.; Song, Y. F.; Smith, L. V.;
Burkholder, E.; Cronin, L. Chem. Commun. 2006, 1194.
8) Due to resonance electron donation, the amidinium moiety
1
32.17 (CH), 130.59 (CH), 129.35 (CH), 123.81 (CH), 123.01
(
(
CH), 122.57 (CH), 119.70 (C), 115.51 (CH), 114.63 (C), 113.06
CH), 39.11 (CH ), 20.33 (CH ).
(
3
3
+
+
of DIP s and IP s makes the positive charge more stable
than the one on the iminium moiety of ordinary
MS (FAB): m/z (%) = 233.3 (M – Br, 100), 178.7 (3), 94.8 (1), 77.1
1).
(
phenanthridinium derivatives and therefore confers better
resistance to the common nucleophilic attack of hydroxide at
physiological pH.
Anal. Calcd for C H N O S: C, 65.55; H, 4.75; N, 6.66. Found: C,
24
24
2
3
6
5.58; H, 4.53; N, 6.63.
(9) Parenty, A. D. C.; Smith, L. V.; Guthrie, K. M.; Long, D. L.;
1
-(4-Methoxybenzyl)-1H-imidazo[1,2-f] phenanthridinium
Plumb, J.; Brown, R.; Cronin, L. J. Med. Chem. 2005, 4504.
Bromide (10d)
Yield: 780 mg (98%); white powder; mp 169–170 °C.
(10) (a) Guthrie, K. M.; Parenty, A. D. C.; Smith, L. V.; Cronin,
L.; Cooper, A. Biophys. Chem 2007, 126, 117. (b) Smith, L.
V.; Parenty, A. D. C.; Guthrie, K. M.; Plumb, J.; Brown, R.;
Cronin, L. ChemBioChem 2006, 7, 1757. (c) Smith, L. V.;
De la Fuente, J. M.; Guthrie, K. M.; Parenty, A. D. C.;
Cronin, L. New J. Chem. 2005, 29, 1118.
IR (KBr): 3432 (m), 3032 (s), 1613 (s), 1556 (s), 1532 (s), 1516 (s),
–
1
1
465 (s), 1249 (s), 1179 (s), 1029 (s), 803 (m), 758 cm (s).
1
H NMR (DMSO-d , 400 MHz): d = 9.33 (d, J = 2.4 Hz, 1 H), 9.00
d, J = 8.4 Hz, 1 H), 8.97 (d, J = 8.0 Hz, 1 H), 8.71 (d, J = 8.0 Hz, 1
6
(
(
(
(
(
11) Parenty, A. D. C.; Smith, L. V.; Cronin, L. Tetrahedron
005, 61, 8410.
12) Kearney, A. M.; Vanderwal, C. D. Angew. Chem. Int. Ed.
006, 45, 7803.
H), 8.53 (d, J = 8.0 Hz, 1 H), 8.40 (d, J = 2.4 Hz, 1 H), 8.01 (m, 2
H), 7.89 (t, J = 7.4 Hz, 1 H), 7.84 (t, J = 7.4 Hz, 1 H), 7.32 (d,
J = 8.0 Hz, 2 H), 7.16 (m, 1 H), 7.12 (m, 1 H), 6.97 (d, J = 8.8 Hz,
2
2
2
H), 6.14 (s, 2 H), 3.74 (s, 3 H).
13) Parenty, A. D. C.; Song, Y. F.; Richmond, C.; Cronin, L.
1
3
Org. Lett. 2007, 9, 2253.
C NMR (DMSO-d , 100 MHz): d = 159.17 (C), 136.38 (C),
6
14) The quantity of electrophilic reactant added in excess
depends on its physical properties: 20 equivalents were used
with low boiling point inexpensive material, whereas only 2
equivalents were necessary with solid starting material.
15) With the exception of the electrophile HBr, where r.t.
conditions and only 1 min stirring were used on 1 mL of a
1
1
1
1
32.37 (CH), 130.88 (CH), 130.01 (C), 129.55 (C), 129.49 (CH),
28.40 (CH), 128.30 (CH), 126.91 (CH), 125.53 (C), 125.31 (CH),
24.80 (CH), 124.19 (CH), 121.69 (C), 117.40 (CH), 116.48 (C),
15.06 (CH), 114.46 (CH), 55.14 (CH ), 53.48 (CH ).
3
2
(
MS (FAB): m/z (%) = 339.3 (M – Br, 100), 231.3 (4), 219.4 (10),
55.0 (18), 122.4 (50), 90.9 (8), 79.0 (8).
1
48% HBr aqueous solution.
Synthesis 2008, No. 1, 155–160 © Thieme Stuttgart · New York