Synthesis of pyrido[3,4-c][1,9]phenanthroline - A five-step procedure to a novel N-containing ring skeleton

Article abstract of DOI:10.1055/s-0032-1318365

The condensation of paraformaldehyde with two equivalents of 4-methylpyridine-3-carbonitrile under basic conditions afforded 6-amino-11,12-dihydropyrido[3,4-c][1,9]phenanthroline, which was converted via the corresponding 6-oxo- and 6-chloro derivatives- and a dehalogenation into 11,12-dihydropyrido[3,4-c][1,9]phenanthroline. The fully aromatized derivative pyrido[3,4-c][1,9]phenanthroline was obtained in an ultimate dehydrogenation procedure. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0032-1318365

SHORT PAPER
▌893
short paper
Synthesis of Pyrido[3,4-c][1,9]phenanthroline – A Five-Step Procedure to a
Novel N-Containing Ring Skeleton
Pyrido[3,4-c][1,9]phenanthroline
Christopher Meier, Philip Sömmer, Ulrich Girreser, Bernd Clement*
Pharmaceutical Institute, Department of Pharmaceutical Chemistry, Christian Albrechts University of Kiel, Gutenbergstraße 76, 24118 Kiel,
Germany
Fax +49(431)8801352; E-mail: bclement@pharmazie.uni-kiel.de
Received: 18.01.2013; Accepted after revision: 12.02.2013
R
Abstract: The condensation of paraformaldehyde with two equiva-
lents of 4-methylpyridine-3-carbonitrile under basic conditions af-
forded 6-amino-11,12-dihydropyrido[3,4-c][1,9]phenanthroline,
which was converted via the corresponding 6-oxo- and 6-chloro
derivatives and a dehalogenation into 11,12-dihydropyrido[3,4-
c][1,9]phenanthroline. The fully aromatized derivative pyrido[3,4-
c][1,9]phenanthroline was obtained in an ultimate dehydrogenation
procedure.
CN
KOt-Bu
N
R
O
DMPU
+
2
25–40 °C
19–69%
H
N
N
N
6
7
8
NH2
reflux
58–89%
Pd/C
DMPU
Key words: antitumor agents, condensation, dehydrogenation, het-
erocycles, phenanthrolines, ring closure
R
R = H, alkyl, aryl
N
N
N
A multitude of N-containing tetracyclic systems based on
the chrysene skeleton have been discovered and synthe-
sized by now. Some of them possess important pharmaco-
logical properties, primarily the benzo[c]phenanthridine
class, which plays a fundamental role in the development
of new anticancer drugs.1 In contrast, there are only few
data dealing with the access to chrysenoid heterocycles
containing three nitrogen atoms in the basic tetracycle
(Figure 1).2–5
9
NH2
Scheme 1 Synthesis of 11-substituted 6-aminopyrido[3,4-c][1,9]phen-
anthrolines 9 and the corresponding 11,12-dihydro derivatives 8
(DMPU = 1,3-dimethyltetrahydropyrimidin-2-one)
nificantly reduced lipophilicity and a superior pH-depen-
dent solubility in aqueous media compared to the C-
analogous 6-aminobenzo[c]phenanthridine derivatives
due to two additional nitrogen atoms embedded in the tet-
racyclic skeleton.6 Moreover, certain derivatives of these
series showed remarkable antitumor activities against hu-
man tumor cell lines (IC50-values <1 μM).6
N
N
N
N
N
Y
N
N
N
N
1
2
3
In this work, we present a short five-step synthetic route
to the previously unknown basic heterocycle pyrido[3,4-
c][1,9]phenanthroline (15), a substance of heterocyclic
and pharmacological interest regarding a possible antitu-
mor activity.
X
1 pyrazino[2,3-i]phenanthridine2
2 pyrido[3,2-c][1,10]phenanthroline3
3 pyridazino[4,5-c]phenanthridine4
4 X = N, Y = CH: pyrido[3,4-c][1,6]phenanthroline5
5 X = CH, Y = N: pyrido[3,4-c][1,7]phenanthroline5
N
N
.
Commercially available starting materials 4-methylpyri-
dine-3-carbonitrile (6) (2 equiv) and paraformaldehyde
(10) were condensed in a two-fold ring-closure reaction
under strongly alkaline conditions to form 6-amino-
11,12-dihydropyrido[3,4-c][1,9]phenanthroline (11) in
29% yield (Scheme 2).6,7 The subsequent step consisted of
a diazotation reaction using NaNO2 and H3PO2 in an acid-
ic aqueous medium giving 5,6,11,12-tetrahydropyri-
do[3,4-c][1,9]phenanthrolin-6-one (12) in good yield
(74%).8 The exchange of the amino moiety in the 6-posi-
tion by an oxo group instead of hydrogen was not surpris-
ing as it had already been reported for 2-aminopyridine
and the phenanthridine ring system.9 The reaction of 12 in
POCl3 under reflux yielded the corresponding 6-chloro
derivative 13,10 which was derivatized to 11,12-dihydro-
pyrido[3,4-c][1,9]phenanthroline (14) in a facile nucleo-
4, 5
Figure 1 Chrysene-like heterocycles containing three nitrogen at-
oms
Recently, we have described the synthesis of various pre-
viously unmentioned 11-substituted 6-aminopyrido[3,4-
c][1,9]phenanthrolines and the corresponding 11,12-di-
hydro derivatives (Scheme 1).
This substance class provides promising improvements
regarding physicochemical properties, as it exhibits sig-
SYNTHESIS 2013, 45, 0893–0895
Advanced online publication: 27.02.2013
DOI: 10.1055/s-0032-1318365; Art ID: SS-2013-T0047-OP
© Georg Thieme Verlag Stuttgart · New York
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X

894
C. Meier et al.
SHORT PAPER
6-Amino-11,12-dihydropyrido[3,4-c][1,9]phenanthroline (11)
A solution of 10 (63 mg, 2.1 mmol) and 6 (500 mg, 4.2 mmol) in
DMPU (10 mL) was added dropwise to a solution of t-BuOK (500
mg, 4.4 mmol) in DMPU (5 mL) while the solution was magnetical-
ly stirred under N2 at r.t. The mixture was stirred for 3 h and then
hydrolyzed with ice water (80 mL). The aqueous solution was
brought to pH 2 with concd HCl and the DMPU was washed out by
extraction with CH2Cl2 (3 × 50 mL). After basification of the aque-
ous phase with concd ammonia solution, the formed precipitate was
filtered off, and the filtrate was extracted with CH2Cl2 (3 × 50 mL).
The combined organic extracts were dried (Na2SO4) and concentrat-
ed in vacuo to afford the crude product. The crude product was pu-
rified by flash column chromatography (silica gel, CH2Cl2–MeOH,
5–20%) to give 11 (150 mg, 29%) as a yellow solid; mp >310 °C.
philic aromatic substitution of the chlorine atom in the 6-
position by hydrogen using ammonium formate in metha-
nol.11 Total aromatization was achieved by heating 14
with 10% Pd/charcoal in DMPU for 10 minutes whereby
the target molecule pyrido[3,4-c][1,9]phenanthroline (15)
was obtained in 70% yield (Scheme 2).6
H
KOt-Bu
DMPU
CN
N
N
N
H
O
2
+
r.t.
29%
N
N
N
N
H
N
11
10
6
NH2
IR (ATR): 3306, 3136, 1670, 1612, 1568, 1462 cm–1.
1H NMR (300 MHz, DMSO-d6): δ = 3.01 (m, 4 H, CH2CH2), 7.29
NaNO2
H3PO2
H2SO4
H
H
3
(br s, 2 H, NH2), 7.33 (d, J = 4.9 Hz, 1 H, ArH), 7.77 (d, 3J = 5.8
Hz, 1 H, ArH), 8.45 (d, 3J = 4.9 Hz, 1 H, ArH), 8.64 (d, 3J = 5.9 Hz,
POCl3
N
1 H, ArH), 9.27 (s, 1 H, ArH), 9.55 (s, 1 H, ArH).
AcOH
0 °C
74%
reflux
43%
N
NH
N
13C NMR [75 MHz, DMSO-d6 + DCl (36%) in D2O]: δ = 20.9 (C-
11), 28.8 (C-12), 116.9 (C-6a), 120.1 (C-10b), 123.9 (C-10), 128.8
(C-1), 129.0 (C-4a), 138.2 (C-4), 139.3 (C-4b), 142.4 (C-9), 144.0
(C-2), 145.5 (C-7), 147.7 (C-10a), 156.8 (C-6), 162.6 (C-12a).
MS (ESI): m/z (%) = 249 ([M + H]+, 92), 125 ([M + 2 H]++, 100).
HRMS (ESI): m/z calcd for [M + H]+: 249.11346; found:
13
15
12
14
O
Cl
H
Pd/C
DMPU
HCO2NH4
MeOH
N
reflux
70%
reflux
60%
249.11319.
N
N
N
5,6,11,12-Tetrahydropyrido[3,4-c][1,9]phenanthrolin-6-one
(12)
Scheme 2 Synthesis of pyrido[3,4-c][1,9]phenanthroline (15)
A 3 N H2SO4 solution (5 mL) was cooled to 0 °C and consecutively
NaNO2 (250 mg, 3.6 mmol, 3-fold excess) and H3PO2 solution (1
mL, 50 wt% in H2O) were added. A second solution consisting of
11 (300 mg, 1.2 mmol) in glacial AcOH (5 mL) and H2O (2 mL)
was added dropwise to the first solution. After the addition of
CuSO4 (3 g, 19 mmol), the mixture was magnetically stirred at 0 °C
for 1 h. The mixture was filtered after 24 h of storage at 4–7 °C and
the filtrate was basified with concd ammonia solution to pH 9 giv-
ing a deep blue solution. The formed precipitate was collected by
filtration, washed with H2O (3 × 50 mL), and dried in vacuo for 24
h. Purification was carried out by flash column chromatography
(silica gel, CH2Cl2–MeOH, 5–20%) to give 12 (202 mg, 74%) as a
pale yellow solid; mp 285 °C (dec.).
Although the 4% overall yield of 15 is quite low, the
method reported herein is an easy way for the synthesis of
the novel heteroaromatic ring system pyrido[3,4-
c][1,9]phenanthroline (15). The total yield is limited by
the first step and the chlorination procedure (step 3). Fu-
ture studies will deal with the optimization of the yields,
especially utilizing microwave-assistance. Preliminary re-
sults displayed a yield of 71% for 13 on performing the
third step under microwave irradiation (CMS, 100 °C, 2
h). The pharmacological properties of 14 and 15 are cur-
rently being investigated.
IR (ATR): 3013, 1643, 1619, 1586, 1556, 1422, 1288 cm–1.
1H NMR [300 MHz, DMSO-d6 + DCl (36%) in D2O]: δ = 3.01 (t,
3
3J = 7.6 Hz, 1 H, H-12), 3.23 (t, J = 7.6 Hz, 1 H, H-11), 8.02 (d,
All reactions were carried out in oven-dried glassware. All commer-
cial reagents were used without purification. The solvents (except
DMPU and POCl3) were freshly distilled. For conventional micro-
wave synthesis (CMS) a CEM Discover system was used in closed
vessel mode. Purification of the products was carried out on a Combi-
Flash Rf, version 1.8.2, flash-chromatography apparatus using
Interchim PF-30SIHP-JP/40G or 12G silica gel columns. Melting
points were determined on a Stuart Scientific SMP3 melting point
3
3J = 5.9 Hz, 1 H, ArH), 8.28 (d, J = 6.8 Hz, 1 H, ArH), 8.71 (d,
3J = 5.9 Hz, 1 H, ArH), 8.74 (d, 3J = 6.9 Hz, 1 H, ArH), 9.23 (s, 1
H, ArH), 9.39 (s, 1 H, ArH).
13C NMR [75 MHz, DMSO-d6 + DCl (36%) in D2O]: δ = 15.6 (C-
11), 24.0 (C-12), 109.4 (C-10b), 118.2 (C-9), 119.1 (C-6a), 123.5
(C-1), 123.8 (C-4a), 133.4 (C-4), 135.1 (C-4b), 137.0 (C-8), 138.5
(C-2), 139.7 (C-7), 144.7 (C-10a), 156.7 (C-12a), 157.1 (C-6).
1
apparatus, and are uncorrected. H and 13C NMR spectra were re-
MS (ESI): m/z (%) = 250 ([M + H]+, 100), 125 ([M + 2 H]++, 53).
corded on a Bruker Avance III 300 instrument at 300 K. Chemical
shifts are given in ppm relative to solvent residual peaks. Signal as-
signments were performed with the help of 1H NMR and 13C HSQC
and HMBC spectra. Mass spectra were recorded on a Bruker Es-
quire LC instrument under ESI conditions. IR spectra were recorded
on a PerkinElmer Spectrum 100 FTIR instrument with ATR attach-
ment. High-resolution mass spectra were recorded on a Bruker
APEX II spectrometer in ESI-positive mode at the Institute of Ana-
lytical Chemistry, University of Leipzig. Elemental analysis was
performed by the Department of Inorganic Chemistry, Christian
Albrechts University of Kiel with a CHNS Analyzator of HEKA-
tech GmbH.
HRMS (ESI): m/z calcd for [M + H]+: 250.09749; found:
250.09747.
6-Chloro-11,12-dihydropyrido[3,4-c][1,9]phenanthroline (13)
To a solution of 12 (100 mg, 0.4 mmol) suspended in POCl3 (5 mL)
were carefully added a few drops of concd HCl while magnetically
stirring until the mixture became a clear solution. Having refluxed
the solution for 2 h, it was carefully hydrolyzed with ice water (50
mL). The solution was slowly adjusted to pH 9 using concd ammo-
nia solution while the temperature was kept below 10 °C. The pre-
cipitate formed was filtered and washed with H2O (2 × 10 mL). The
crude product was purified by flash column chromatography (silica
Synthesis 2013, 45, 893–895
© Georg Thieme Verlag Stuttgart · New York

SHORT PAPER
Pyrido[3,4-c][1,9]phenanthroline
895
gel, CH2Cl2–MeOH, 0–10%) to afford 13 (46 mg, 43%) as an off-
IR (ATR): 2962, 1615, 1599, 1571, 1398, 1259, 1070 cm–1.
white solid; mp 227 °C (dec.).
IR (ATR): 2851, 1614, 1592, 1562, 1418, 1392, 1071 cm–1.
1H NMR (300 MHz, DMSO-d6–CF3CO2D, 5:1): δ = 8.62 (d,
3
3J = 9.1 Hz, 1 H, H-12), 8.76 (d, J = 6.4 Hz, 1 H, H-1), 9.22 (d,
3
3J = 6.3 Hz, 1 H, H-9), 9.24 (d, J = 6.3 Hz, 1 H, H-10), 9.53 (d,
1H NMR (300 MHz, CDCl3): δ = 3.10 (t, 3J = 7.8 Hz, 2 H, H-12),
3.29 (m, 2 H, H-11), 7.21 (dd, 3J = 5.0 Hz, 5J = 0.8 Hz, 1 H, H-1),
7.78 (dd, 3J = 6.0 Hz, 5J = 1.0 Hz, 1 H, H-10), 8.56 (d, 3J = 5.0 Hz,
1 H, H-2), 8.84 (d, 3J = 6.0 Hz, 1 H, H-9), 9.47 (s, 1 H, H-4), 9.73
(d, 5J = 1.0 Hz, 1 H, H-7).
13C NMR (75 MHz, CDCl3): δ = 21.4 (C-11), 26.4 (C-12), 115.3
(C-10), 121.1 (C-6a), 122.4 (C-1), 123.7 (C-10b), 128.9 (C-4a),
139.9 (C-10a), 145.6 (C-12a), 146.8 (C-4b), 147.2 (C-4), 148.3 (C-
9), 150.5 (C-2), 150.9 (C-6), 152.1 (C-7).
3
3J = 9.1 Hz, 1 H, H-11), 9.84 (d, J = 6.4 Hz, 1 H, H-2), 10.09,
10.11, 10.75 (3 s, 1 H, H-6, H-7, H-4).
13C NMR (75 MHz, DMSO-d6–CF3CO2D, 5:1): δ = 119.4 (C-10),
121.5 (C-10b), 122.5 (C-6a), 125.6 (C-1), 126.1 (C-4a), 127.5 (C-
12), 132.2 (C-11), 136.3 (C-2), 138.8 (C-10a), 141.8 (C-12a), 143.8
(C-9), 144.2 (C-4b), 144.5 (C-4), 150.9 (C-7), 155.5 (C-6).
15N NMR [30 MHz, DMSO-d6–CF3CO2D (5:1) + 0.2% MeNO2
(external standard in DMSO-d6)]: δ = –79.9 (N-5), –128.1 (N-8),
–177.3 (N-3).
MS (ESI): m/z (%) = 268 ([M + H]+, 35Cl, 100), 270 ([M + H]+, 37Cl,
31).
MS (ESI): m/z = 232 ([M + H]+, 100%).
HRMS (ESI): m/z calcd for [M + H]+: 268.06360; found:
HRMS (ESI): m/z calcd for [M + H]+: 232.08692; found:
268.06383.
232.08707.
Anal. Calcd for C15H9N3·1.5 H2O: C, 69.76; H, 4.68; N, 16.27.
Found: C, 69.29; H, 4.20; N, 15.92.
11,12-Dihydropyrido[3,4-c][1,9]phenanthroline (14)
Compound 13 (100 mg, 0.37 mmol) was dissolved in MeOH (200
mL), and ammonium formate (200 mg, 3.17 mmol) and 10% Pd/C
(50 mg) were added. The solution was refluxed for 1 h. Pd/C was
filtered off and the filtrate was evaporated to dryness. Purification
of the crude product was carried out by flash column chromatogra-
phy (silica gel, CH2Cl2–MeOH, 5–20%). Product 14 was obtained
as a white solid (53 mg, 60%); mp 235 °C.
References
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Clement, B. J. Med. Chem. 2005, 48, 2772. (b) Clement, B.;
Weide, M.; Wolschendorf, U.; Kock, I. Angew. Chem. Int.
Ed. 2005, 44, 635.
IR (ATR): 3051, 3013, 1613, 1598, 1570, 1493, 1039 cm–1.
1H NMR (300 MHz, CDCl3): δ = 3.09 (t, 3J = 7.4 Hz, 2 H, H-12a,b),
3.31 (t, 3J = 7.4 Hz, 2 H, H-11a,b), 7.22 (d, 3J = 4.9 Hz, 1 H, H-1),
7.80 (d, 3J = 6.1 Hz, 1 H, H-10,), 8.58 (d, 3J = 4.9 Hz, 1 H, H-10),
8.78 (d, 3J = 6.1 Hz, 1 H, H-9), 9.37 (s, 1 H, H-6), 9.41 (s, 1 H, H-
7), 9.58 (s, 1 H, H-4).
13C NMR (75 MHz, CDCl3): δ = 21.6 (C-11), 26.9 (C-12), 115.4
(C-10), 122.5 (C-1), 123.0 (C-6a), 123.9 (C-10b), 130.0 (C-4a),
137.4 (C-10a), 145.7 (C-12a), 147.3 (C-4), 147.5 (2 C, C-4b, C-9),
150.2 (C-2) 151.5 (C-6) 153.4 (C-7).
MS (ESI): m/z = 234 ([M + H]+, 100%).
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University of Kiel: Germany, 2003. (b) Kornblum, N. Org.
React. 1944, 2, 262.
HRMS (ESI): m/z calcd for [M + H]+: 234.10257; found:
234.10271.
(9) (a) Engel, A. In Houben-Weyl, Methods of Organic
Chemistry; Vol. E 16a, Part II; Klamann, D., Ed.; Thieme:
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Tetrahedron 2006, 63, 71.
Pyrido[3,4-c][1,9]phenanthroline (15)
Compound 14 (50 mg, 0.21 mmol) was dissolved in DMPU (7 mL)
and 10% Pd/C (25 mg) was added. After refluxing the solution un-
der N2 for 10 min, the reaction vessel was washed with CH2Cl2 (50
mL), Pd/C was filtered off, and the filtrate was extracted with 5%
aq HCl (3 × 20 mL). The aqueous phases were combined and
brought to pH 9 with concd ammonia solution while magnetically
stirring. The generated precipitate was filtered and purified by col-
umn chromatography (silica gel, CH2Cl2–MeOH, 10%). Product 15
was obtained as a white solid (35 mg, 70%); mp 265 °C.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 893–895