Facile and convenient syntheses of fluorine-containing pyrido[2,3- h ]-quinazolines and 1,7-phenanthrolines by condensation reactions of 6,8-bis(trifluoroacetyl)quinolin-5-amine with carbonyl compounds

Article abstract of DOI:10.1055/s-0030-1260133

6,8-Bis(trifluoroacetyl)quinolin-5-amine reacted easily with various aldehydes in the presence of aqueous ammonia to afford trifluoromethylated pyrido[2,3-h]quinazoline derivatives and 1,7-phenanthroline derivatives in good to excellent yields. Under almo

Full text of DOI:10.1055/s-0030-1260133

2754
PAPER
Facile and Convenient Syntheses of Fluorine-Containing Pyrido[2,3-h]-
quinazolines and 1,7-Phenanthrolines by Condensation Reactions of
6,8-Bis(trifluoroacetyl)quinolin-5-amine with Carbonyl Compounds
P
yrido[2, 3-
h
]quinazoli
a
nes and 1,7
m
-Phenanthrolines oru Hinoshita,a Dai Shibata,b Mizuki Hatakenaka,a Etsuji Okada*a
a
Kobe 657-8501, Japan
Fax +81(78)8036194; E-mail: okaetsu@kobe-u.ac.jp
Graduate School of Science and Technology, Kobe University, Rokkodai-cho, Nada-ku, Kobe 657-8501, Japan
b
Received 21 April 2011; revised 2 June 2011
would be expected to present new activities or functional-
ities.
Abstract: 6,8-Bis(trifluoroacetyl)quinolin-5-amine reacted easily
with various aldehydes in the presence of aqueous ammonia to af-
ford trifluoromethylated pyrido[2,3-h]quinazoline derivatives and
1,7-phenanthroline derivatives in good to excellent yields. Under
almost the same conditions, the use of ketones instead of aldehydes
gave 1,7-phenanthroline derivatives selectively, except in the case
of cyclohexanone.
Previously, we have reported facile synthetic methods of
novel heterocycles bearing CF3 groups using our original-
ly developed fluorine-containing building blocks.8 For
example, trifluoroacetylated naphthalen-1-amine and
quinolin-8-amine were utilized in the syntheses of naph-
thalene- and quinoline-fused heterocycles by three-com-
ponent condensation reactions and pyridine-ring
formation reactions.9 More recently, we also described a
convenient synthesis of trifluoromethylated 1,7-phenan-
throline derivatives by cyclization reactions of N-propar-
Key words: pyrido[2,3-h]quinazolines, 1,7-phenanthrolines, fluo-
rine, condensation reaction, quinolin-5-amines
In recent years, the development of new methodologies
for the synthesis of many kinds of fluorine-containing het-
erocycles has been the subject of much attention because
of their importance and potential as the organic materials
showing interesting biological activities in medicinal and
agricultural scientific fields.1
gylquinolin-5-amine
derivative
with
various
nucleophiles.10 This fluorine-containing building block of
a quinolin-5-amine system was easily synthesized by a
SNAr of N,N-dimethyl-6,8-bis(trifluoroacetyl)quinolin-5-
amine (1) with propargylamine.
Meanwhile, it is common knowledge that heterocyclic
compounds that have pyridine and pyrimidine skeletons
are important systems that are encountered in a number of
natural products and have wide applications for a variety
of purposes such as biological materials, drugs, and agro-
chemicals in particular.2 From this viewpoint, pyrido[2,3-
h]quinazolines contain both pyridine and pyrimidine skel-
etons, and have prospective structure for these purposes.
However, a literature survey showed that there are only a
few methods for the preparation of pyrido[2,3-h]quinazo-
line derivatives,3 to say nothing about fluorine-containing
derivatives.
In continuation of our work, 6,8-bis(trifluoroacetyl)quin-
olin-5-amine (2) was synthesized and used as a new fluo-
rine-containing building block, and herein we wish to
present an efficient and convenient synthesis of the title
compounds 3–7. That is to say, 2 underwent the three-
component condensation reaction with aldehydes in the
presence of aqueous ammonia to give the pyrido[2,3-
h]quinazoline derivatives 3 and 4, and in the case of ali-
phatic aldehydes, 1,7-phenanthroline derivatives 5 were
also obtained by Friedländer-type cyclization. Under the
quite similar conditions, the reaction of 2 with ketones
gave 1,7-phenanthroline derivatives 6 selectively. As
Similarly, 1,7-phenanthrolines have attracted much atten- identified above, these novel fluorinated compounds are
tion because of their biological properties. For example, powerfully expected to show interesting biological prop-
they have demonstrated potential applications as topoi- erties.
somerase I inhibitors with cytotoxic properties towards
The new fluorine-containing building block 2 was easily
synthesized in high yield by the dimethylamino–amino
exchange reaction of N,N-dimethyl-6,8-bis(trifluoro-
acetyl)quinolin-5-amine (1) with aqueous ammonia.
L1210 murine leukemia cells,4 antimalarials,5 and telom-
erase inhibitors.6 Besides, they have also been shown to
be applicable in host-guest chemistry.7 However, fluori-
nated 1,7-phenanthroline derivatives are rarely known.
Because of these reasons, it is of synthetic value to devel-
Compound 1 was readily prepared in three steps by reduc-
tion,11 N,N-dimethylation,12 and bis(trifluoroacetylation)
op facile synthetic methods to fluorine-containing pyri-
from commercially available 5-nitroquinoline (Scheme 1).
do[2,3-h]quinazolines and 1,7-phenanthrolines, which
The results from the reaction of 2 with various aldehydes
are shown in Scheme 2 and summarized in Table 1. The
SYNTHESIS 2011, No. 17, pp 2754–2760
Advanced online publication: 21.07.2011
DOI: 10.1055/s-0030-1260133; Art ID: F42611SS
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x
.
2
0
1
1
three-component condensation reaction of 2 with acetal-
dehyde in the presence of aqueous ammonia proceeded
quickly at 50 °C in acetonitrile to give the corresponding

PAPER
Pyrido[2,3-h]quinazolines and 1,7-Phenanthrolines
2755
NMe2
NH2
R1
R1
COCF3
COCF3
aq NH3
82%
HN
N
N
N
N
N
DDQ (1 equiv)
MeCN, r.t., 2 h
CF3
CF3
COCF3
COCF3
N
N
1
2
C(OH)2CF3
C(OH)2CF3
Scheme 1
4a: R1 = Me; 84%
4b: R1 = Et; 64%
4c: R1 = i-Pr; 99%
3a–c
fluorine-containing dihydropyrido[2,3-h]quinazoline 3a,
which is the precursor of expected pyrido[2,3-h]quinazo-
line 4a, in 48% yield, together with 1,7-phenanthroline
derivative 5a in 24% yield (Table 1, entry 1). The latter
product 5a would be formed by Friedländer-type cycliza-
tion,13 in which the ammonia works not as a nucleophile
but as a base. Similarly in the case of propionaldehyde, 3b
and 5b were obtained in 48% and 16% yields, respectively
(entry 2). Isobutyraldehyde also reacted to afford 3c ex-
clusively and Friedländer-type cyclization had not oc-
curred due to difficulty of deprotonation at sterically
hindered a-position (entry 3). Interestingly, the reaction
of 2 with aromatic aldehydes, such as p-substituted benz-
aldehydes and aqueous ammonia gave mixtures of 3d–g
and 4d–g, respectively, in good combined yields (entries
4–7).
Scheme 3
tion, could be performed easily in a one-pot manner to
give the desired 4d–g in good to high yields (Scheme 4).
The 6-trifluoroacetyl group of the products was found to
exist in the hydrate form and this phenomenon was also
observed in our previous experiments of the quinoline-
fused heterocycle syntheses.8d,9c,d,10
One of the possible mechanistic pathways for the forma-
tion of dihydropyrido[2,3-h]quinazolines 3, pyrido[2,3-
h]quinazolines 4, and 1,7-phenanthrolines 5 is depicted
for the reaction of 2 with acetaldehyde as a representative
case in Scheme 5. Initially, the condensation of amino
group of 2 with acetaldehyde occur to give an aldimine I.
When ammonia works as a nucleophile (path A), an ami-
nal II or a hemiaminal III, or both are formed and the fol-
lowing intramolecular cyclization affords the precursor
3a, which undergoes dehydrogenation by DDQ to give the
final product 4a. On the other hand, when ammonia acts
as a base (path B), the carbanion center of IV generated by
deprotonation at the a-position attacks the carbonyl car-
bon of the trifluoroacetyl group to give 5a.
Treatment of dihydropyrido[2,3-h]quinazolines 3a–c with
DDQ at room temperature for 2 hours led to successful de-
hydrogenation to give fluorine-containing pyrido[2,3-
h]quinazolines 4a–c in 64–99% yield (Scheme 3).
In the case of aromatic aldehydes, the two-step reaction,
the condensation reaction and the following dehydrogena-
Table 1 Three-Component Condensation Reaction of 6,8-Bis(trifluoroacetyl)quinolin-5-amine (2) with Aldehydes and Ammonia
Entry
R1
R2
H
Me
–
Aldehyde, ammonia (equiv)
Time (h)
Product(s)
3a, 5a
3b, 5b
3c
Yield (%)a
48, 24
48, 16
84
1
Me
3
3
3
5
5
5
5
4
24
24
24
24
24
24
2
Et
3
i-Pr
4
4-MeOC6H4
4-MeC6H4
Ph
–
3d, 4d
3e, 4e
3f, 4f
66, 24
38, 49
24, 53
54, 26
5
–
6
–
7
4-ClC6H4
–
3g, 4g
a Isolated yields.
R1
R1
R2
NH2
HN
N
N
N
N
R1CHO
aq NH3
COCF3
CF3
CF3
CF3
+
+
MeCN, 50 °C
N
N
N
N
COCF3
C(OH)2CF3
C(OH)2CF3
C(OH)2CF3
5a,b
2
3a–g
4d–g
Scheme 2
Synthesis 2011, No. 17, 2754–2760 © Thieme Stuttgart · New York

2756
M. Hinoshita et al.
PAPER
R1
one-pot, two-step
NH2
N
N
R1CHO (5 equiv)
aq NH3 (5 equiv)
COCF3
DDQ (1 equiv)
MeCN, r.t., 2 h
CF3
3d–g
MeCN, 50 °C, 24 h
N
N
COCF3
C(OH)2CF3
4d: R1 = 4-MeOC6H4; 62%
4e: R1 = 4-MeC6H4; 74%
4f: R1 = Ph; 91%
2
4g: R1 = 4-ClC6H4; 74%
Scheme 4
Me
N
NH2
COCF3
COCF3
MeCHO
– H2O
N
N
COCF3
COCF3
2
I
Me
Me
Me
Me
N
N
HN
NH2
CF3
O
N
NH2
CF3
OH
HN
N
path A
NH3
(as a nucleophile)
DDQ
– H2
CF3
CF3
– H2O
N
N
N
N
C(OH)2CF3
COCF3
COCF3
C(OH)2CF3
4a
3a
II
III
CH2
CF3
N
N
path B
NH3
(as a base)
CF3
O
– H
– OH
N
N
COCF3
C(OH)2CF3
IV
5a
Scheme 5
Furthermore, the present cyclization reaction was applied (alkyl or aryl)-1,7-phenanthrolines 6c–e in high yield (en-
to a variety of ketones (Scheme 6, Table 2). Reaction of 2 tries 3–5). Although two products were possible in the
with acetone took place cleanly at 50 °C in acetonitrile in case of ethyl methyl ketone, only 2-ethyl derivative 6c
the presence of aqueous ammonia to afford the corre- was obtained selectively. Moreover, the reactions with
sponding 1,7-phenanthroline 6a in high yield without any aliphatic cyclic ketones yielded heterotetracyclic com-
formation of pyrido[2,3-h]quinazoline derivative pounds 6f–h in high yield, except in the case of
(Table 2, entry 1). In the case of diethyl ketone, 6b was cyclohexanone, which afforded spiro-substituted dihydro-
also obtained selectively though a prolonged reaction time pyrido[2,3-h]quinazoline derivative 7 together with 6g. In
and more elevated temperature were necessary (entry 2). our previous report9d on the similar condensation reaction
Similarly, the reaction with asymmetric ketones such as of 5,7-bis(trifluoroacetyl)quinolin-8-amine, we found that
ethyl methyl ketone, isopropyl methyl ketone, and ace- use ethyl methyl ketone, an unsymmetrical acyclic ke-
tophenone, occurred easily to give the corresponding 2- tone, led to the formation of a mixture of the two regioiso-
R3
R4
NH2
N
HN
N
R3COCH2R4
aq NH3
COCF3
CF3
CF3
+
MeCN
N
N
N
COCF3
C(OH)2CF3
COCF3
2
6a–h
7
Scheme 6
Synthesis 2011, No. 17, 2754–2760 © Thieme Stuttgart · New York

PAPER
Pyrido[2,3-h]quinazolines and 1,7-Phenanthrolines
2757
Table 2 Condensation Reaction of 2 with Ketones in the Presence of Aqueous Ammonia
Entry
R3
R4
H
Ketone, ammonia (equiv) Temp ( °C)
Time (h)
24
Product
6a
Yield (%)a
1
2
3
4
5
6
7
8
Me
Et
3
5
5
5
5
3
3
3
50
80b
50
50
50
50
50
50
90
Me
H
72
6b
67
Et
24
6c
85
i-Pr
Ph
H
24
6d
87
H
120
24
6e
85
-(CH2)3-
-(CH2)4-
-(CH2)5-
6f
87
24
6g/7
6h
52/46
87
24
a Isolated yields.
b In a sealed tube.
Three-Component Condensation Reaction of 2 with Aldehydes
in the Presence of Ammonia; General Procedure
mers, 2-ethyl (6c-type) and 2,3-dimethyl substituted 1,10-
phenanthrolines. However, in the case of cyclohexanone,
a symmetrical cyclic ketone, a single product (6g-type)
was obtained without any formation of the spiral com-
pound (7-type). The interesting product selectivity appear
to be specific for the substrates used, when comparing the
results obtained from both systems of 5- and 8-quinolyl-
amines. At the present time it is not clear why these differ-
ences, dependent upon the substrates, have resulted.
The appropriate aldehyde (3 or 5 mmol) and 28% (w/w) aq NH3 (3
or 5 mmol) were added to a solution of 2 (354 mg, 1 mmol) in
MeCN (5 mL), and the mixture was stirred at 50 °C for 4–24 h.
Evaporation of the solvent in vacuo gave a crude mixture, which
was subjected to column chromatography (silica gel, n-hexane–
EtOAc, 6:1 to 2:1) to give the corresponding 3a–g, 4d–g, and 5a,b.
Dehydrogenation of 3a–c with DDQ; General Procedure
DDQ (1.05 mmol) was added to a solution of the appropriate 3a–c
(1 mmol) in MeCN (16 mL), and the mixture was stirred at r.t. for
2 h. The mixture was washed with sat. aq Na2CO3 (20 mL), extract-
ed with EtOAc (80 mL), and the extract was dried (Na2SO4). Evap-
oration of the solvent in vacuo gave the corresponding pure 4a–c.
In summary, we have succeeded in the utilization of 2 as
a new fluorine-containing building block and could
present an efficient and convenient synthetic method for
novel fluorine-containing pyrido[2,3-h]quinazolines 3, 4,
and 7, and 1,7-phenanthrolines 5 and 6, which are not eas-
ily accessible by other methods. Evaluation of biological
activities for 3–7 is now underway.
One-Pot Syntheses of 4d–g; General Procedure
The appropriate aromatic aldehyde (5.00 mmol) and 28% (w/w) aq
NH3 (5.00 mmol) were added to a solution of 2 (354 mg, 1.00
mmol) in MeCN (5 mL), and the mixture was stirred at 50 °C for 24
h. The solvent was removed under reduced pressure, and MeCN (16
mL) was added to the residue. DDQ (1.05 mmol) was added to the
solution, and the mixture was stirred at r.t. for 2 h. The mixture was
washed with sat. aq Na2CO3 (20 mL), extracted with EtOAc (80
mL), and the extract was dried (Na2SO4). Evaporation of the solvent
in vacuo gave a crude mixture, which was subjected to column chro-
matography (silica gel, n-hexane–EtOAc, 2:1) to give the corre-
sponding 4d–g.
Melting points were determined on an electrothermal digital melt-
ing point apparatus and are uncorrected. 1H NMR spectra were mea-
sured on a Bruker Avance 500 spectrometer (at 500 MHz); TMS
was used as an internal standard. IR spectra were recorded on a
PerkinElmer Spectrum ONE spectrophotometer. Microanalyses
were obtained with a Yanaco CHN-Coder MT-5 analyzer.
6,8-Bis(trifluoroacetyl)quinolin-5-amine (2)
A solution of 28% (w/w) aq NH3 (2.7 mL, 40 mmol) and N,N-di-
methyl-6,8-bis(trifluoroacetyl)quinolin-5-amine (1;10–12 1.46 g, 4
mmol) in MeCN (32 mL) was heated in a sealed tube at 80 °C for 4
h. After removal of the solvent, the crude mixture was subjected to
column chromatography (silica gel, n-hexane–EtOAc, 4:1) to give
2; yield: 1.16 g (82%); mp 220 °C (n-hexane–EtOAc).
2,2,2-Trifluoro-1-(2-methyl-4-trifluoromethyl-1,2-dihydropyri-
do[2,3-h]quinazolin-6-yl)ethane-1,1-diol (3a)
Mp 175–176 °C (n-hexane–EtOAc).
IR (KBr): 3380 cm–1.
1H NMR (CD3CN–CDCl3): d = 8.97 (d, J = 4.0 Hz, 1 H, H-8), 8.46
(d, J = 8.5 Hz, 1 H, H-10), 8.05 (s, 1 H, H-5), 7.54–7.51 (m, 1 H, H-
9), 7.45 (br s, 2 H, OH), 6.85–6.67, 6.07 (br s, 1 H, NH), 5.59, 5.37
(q, J = 6.0 Hz, 1 H, H-2), 1.65–1.63 (m, 3 H, CH3).
IR (KBr): 3520, 3323, 1662, 1623 cm–1.
1H NMR (CDCl3): d (monohydrate form) = 8.89 (d, J = 4.5 Hz, 1 H,
H-2), 8.60–8.03 (br, 2 H, NH or OH), 8.56 (d, J = 9.0 Hz, 1 H, H-
4), 8.40 (s, 1 H, H-7), 7.63 (br s, 2 H, NH or OH), 7.54 (dd, J = 4.5,
9.0 Hz, 1 H, H-3).
Anal. Calcd for C15H11F6N3O2 (379.1): C, 47.50; H, 2.92; N, 11.08.
Found: C, 47.74; H, 3.00; N, 10.76.
Anal. Calcd for C13H8F6N2O3 (354.0) (monohydrate form): C,
44.08; H, 2.28; N, 7.91. Found: C, 43.90; H, 2.48; N, 7.68.
1-(2-Ethyl-4-trifluoromethyl-1,2-dihydropyrido[2,3-h]quinazo-
lin-6-yl)-2,2,2-trifluoroethane-1,1-diol (3b)
Mp 158–159 °C (n-hexane–EtOAc).
IR (KBr): 3385, 3323 cm–1.
Synthesis 2011, No. 17, 2754–2760 © Thieme Stuttgart · New York

2758
M. Hinoshita et al.
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2,2,2-Trifluoro-1-(2-methyl-4-trifluoromethylpyrido[2,3-
h]quinazolin-6-yl)ethane-1,1-diol (4a)
Mp 201–202 °C (n-hexane–EtOAc).
1H NMR (CD3CN): d = 9.26–7.45 (br, 2 H, OH), 9.00 (d, J = 4.0
Hz, 1 H, H-8), 8.73 (d, J = 9.0 Hz, 1 H, H-10), 8.18 (br s, 1 H, H-5),
7.67 (dd, J = 4.0, 9.0 Hz, 1 H, H-9), 7.05–6.63, 6.40–6.05 (br, 1 H,
NH), 5.62–5.15 (m, 1 H, CH), 2.33–1.72 (m, 2 H, CH2), 1.10 (t,
J = 7.0 Hz, 3 H, CH3).
IR (KBr): 3323, 3093 cm–1.
1H NMR (DMSO-d6–CDCl3): d = 9.83 (dd, J = 2.0, 8.0 Hz, 1 H, H-
10), 9.43 (s, 2 H, OH), 9.27 (dd, J = 2.0, 4.0 Hz, 1 H, H-8), 8.95 (br
s, 1 H, H-5), 8.00 (dd, J = 4.0, 8.0 Hz, 1 H, H-9), 3.10 (s, 3 H, CH3).
Anal. Calcd for C16H13F6N3O2 (393.1): C, 48.86; H, 3.33; N, 10.68.
Found: C, 49.04; H, 3.34; N, 10.29.
Anal. Calcd for C15H9F6N3O2 (377.1): C, 47.76; H, 2.40; N, 11.14.
Found: C, 47.71; H, 2.43; N, 11.16.
2,2,2-Trifluoro-1-(2-isopropyl-4-trifluoromethyl-1,2-dihydro-
pyrido[2,3-h]quinazolin-6-yl)ethane-1,1-diol (3c)
Mp 165–166 °C (hexane–EtOAc).
IR (KBr): 3389 cm–1.
1H NMR (DMSO-d6–CD3CN): d = 9.08–8.63 (m, 4 H, H-8, H-10,
OH), 8.15 (br s, 1 H, H-5), 7.60 (dd, J = 5.0, 9.0 Hz, 1 H, H-9),
6.87–6.42 (br, 1 H, NH), 5.50–5.17 (m, 1 H, H-2), 2.90–1.87 [m, 1
H, CH(CH3)2], 1.07 (d, J = 7.0 Hz, 6 H, CH3).
1-(2-Ethyl-4-trifluoromethylpyrido[2,3-h]quinazolin-6-yl)-
2,2,2-trifluoroethane-1,1-diol (4b)
Mp 144–145 °C (n-hexane–EtOAc).
IR (KBr): 3350, 3094 cm–1.
1H NMR (CD3CN): d = 9.85 (dd, J = 2.0, 8.0 Hz, 1 H, H-10), 9.28
(dd, J = 2.0, 5.0 Hz, 1 H, H-8), 8.87 (br s, 1 H, H-5), 8.03 (dd,
J = 5.0, 8.0 Hz, 1 H, H-9), 7.28–5.78 (br, 2 H, OH), 3.38 (q, J = 8.0
Hz, 2 H, CH2), 1.57 (t, J = 8.0 Hz, 3 H, CH3).
Anal. Calcd for C17H13F6N3O (389.1) (unhydrated form): C, 52.45;
H, 3.37; N, 10.79. Found: C, 52.76; H, 3.22; N, 10.63.
Anal. Calcd for C16H11F6N3O2 (391.1): C, 49.11; H, 2.83; N, 10.74.
Found: C, 49.46; H, 2.86; N, 10.37.
2,2,2-Trifluoro-1-[2-(4-methoxyphenyl)-4-trifluoromethyl-1,2-
dihydropyrido[2,3-h]quinazolin-6-yl]ethane-1,1-diol (3d)
Mp 162–163 °C (n-hexane–EtOAc).
IR (KBr): 3264 cm–1.
1H NMR (CD3CN): d = 9.02–8.38 (br, 2 H, OH), 8.92 (dd, J = 2.0,
4.0 Hz, 1 H, H-8), 8.63 (dd, J = 2.0, 8.0 Hz, 1 H, H-10), 8.27 (br s,
1 H, H-5), 7.70–7.47 (m, 3 H, H-9, Harom), 7.00 (d, J = 9.0 Hz, 2
2,2,2-Trifluoro-1-(2-isopropyl-4-trifluoromethylpyrido[2,3-
h]quinazolin-6-yl)ethane-1,1-diol (4c)
Mp 155–156 °C (n-hexane–EtOAc).
IR (KBr): 3350, 3092 cm–1.
1H NMR (DMSO-d6–CDCl3): d = 9.95 (dd, J = 2.0, 8.0 Hz, 1 H, H-
10), 9.35 (br s, 2 H, OH), 9.23 (dd, J = 2.0, 4.0 Hz, 1 H, H-8), 8.98
(br s, 1 H, H-5), 7.97 (dd, J = 4.0, 8.0 Hz, 1 H, H-9), 3.63 (hept,
J = 7.0 Hz, 1 H, CH), 1.63 (d, J = 7.0 Hz, 6 H, CH3).
Harom), 6.73 (br s, 1 H, NH), 6.47 (br s, 1 H, H-2), 3.82 (s, 3 H, CH3).
Anal. Calcd for C21H15F6N3O3 (471.1): C, 53.51; H, 3.21; N, 8.91.
Found: C, 53.91; H, 3.17; N, 8.55.
Anal. Calcd for C17H13F6N3O2 (405.1): C, 50.38; H, 3.23; N, 10.37.
Found: C, 50.58; H, 3.32; N, 10.08.
2,2,2-Trifluoro-1-(2-p-tolyl-4-trifluoromethyl-1,2-dihydropyri-
do[2,3-h]quinazolin-6-yl)ethane-1,1-diol (3e)
Mp 174–175 °C (n-hexane–EtOAc).
IR (KBr): 3334 cm–1.
1H NMR (CD3CN): d = 9.03 (dd, J = 2.0, 4.0 Hz, 1 H, H-8), 8.72
(dd, J = 2.0, 9.0 Hz, 1 H, H-10), 8.33 (br s, 1 H, H-5), 7.80–7.28 (m,
5 H, H-9, Harom), 6.80 (br s, 1 H, NH), 6.58 (br s, 1 H, H-2), 6.00–
4.63 (br, 2 H, OH), 2.37 (s, 3 H, CH3).
2,2,2-Trifluoro-1-[2-(4-methoxyphenyl)-4-trifluoromethylpyri-
do[2,3-h]quinazolin-6-yl]ethane-1,1-diol (4d)
Mp 208–209 °C (n-hexane–EtOAc).
IR (KBr): 3356, 3082 cm–1.
1H NMR (DMSO-d6–CD3CN): d = 10.02 (dd, J = 2.0, 8.0 Hz, 1 H,
H-10), 9.62 (s, 2 H, OH), 9.40 (dd, J = 2.0, 5.0 Hz, 1 H, H-8), 8.93–
8.70 (m, 3 H, H-5, Harom), 8.13 (dd, J = 5.0, 8.0 Hz, 1 H, H-9), 7.20
(d, J = 9.0 Hz, 2 Harom), 3.95 (s, 3 H, CH3).
Anal. Calcd for C21H15F6N3O2 (455.1): C, 55.39; H, 3.32; N, 9.23.
Found: C, 55.51; H, 3.37; N, 9.06.
Anal. Calcd for C21H13F6N3O3 (469.1): C, 53.74; H, 2.79; N, 8.95.
Found: C, 53.92; H, 2.86; N, 9.12.
2,2,2-Trifluoro-1-(2-phenyl-4-trifluoromethyl-1,2-dihydropyri-
do[2,3-h]quinazolin-6-yl)ethane-1,1-diol (3f)
Mp 217–218 °C (n-hexane–EtOAc).
IR (KBr): 3305 cm–1.
1H NMR (CD3CN): d = 9.20–8.40 (br, 2 H, OH), 9.00 (dd, J = 2.0,
4.0 Hz, 1 H, H-8), 8.70 (dd, J = 2.0, 9.0 Hz, 1 H, H-10), 8.30 (br s,
1 H, H-5), 7.93–7.33 (m, 6 H, H-9, Harom), 6.80 (br s, 1 H, NH), 6.58
(br s, 1 H, H-2).
2,2,2-Trifluoro-1-(2-p-tolyl-4-trifluoromethylpyrido[2,3-
h]quinazolin-6-yl)ethane-1,1-diol (4e)
Mp 205–206 °C (n-hexane–EtOAc).
IR (KBr): 3319, 3068 cm–1.
1H NMR (DMSO-d6–CDCl3): d = 9.80 (d, J = 8.5 Hz, 1 H, H-10),
9.06 (d, J = 4.5 Hz, 1 H, H-8), 8.93 (br s, 2 H, OH), 8.84 (s, 1 H, H-
5), 8.62 (d, J = 8.0 Hz, 2 Harom), 7.81 (dd, J = 4.5, 8.5 Hz, 1 H, H-9),
7.37 (d, J = 8.0 Hz, 2 Harom), 2.47 (s, 3 H, CH3).
Anal. Calcd for C20H13F6N3O2 (441.1): C, 54.43; H, 2.97; N, 9.52.
Found: C, 54.60; H, 3.18; N, 9.13.
Anal. Calcd for C21H13F6N3O2 (453.1): C, 55.64; H, 2.89; N, 9.27.
Found: C, 55.67; H, 2.97; N, 9.16.
1-(2-(4-Chlorophenyl)-4-trifluoromethyl-1,2-dihydropyri-
do[2,3-h]quinazolin-6-yl)-2,2,2-trifluoroethane-1,1-diol (3g)
Mp 156–157 °C (n-hexane–EtOAc).
IR (KBr): 3381 cm–1.
1H NMR (CD3CN): d = 8.92 (dd, J = 2.0, 4.0 Hz, 1 H, H-8), 8.63
(dd, J = 2.0, 9.0 Hz, 1 H, H-10), 8.22 (br s, 1 H, H-5), 7.72–7.33 (m,
5 H, H-9, Harom), 6.75 (br s, 1 H, NH), 6.48 (br s, 1 H, H-2).
2,2,2-Trifluoro-1-(2-phenyl-4-trifluoromethylpyrido[2,3-
h]quinazolin-6-yl)ethane-1,1-diol (4f)
Mp 189–190 °C (n-hexane–EtOAc).
IR (KBr): 3350, 3073 cm–1.
1H NMR (DMSO-d6–CDCl3): d = 9.85 (d, J = 8.5 Hz, 1 H, H-10),
9.09 (d, J = 4.0 Hz, 1 H, H-8), 8.94 (br s, 2 H, OH), 8.87 (s, 1 H, H-
5), 7.85 (dd, J = 4.0, 8.5 Hz, 1 H, H-9), 7.59 (br s, 5 Harom).
Anal. Calcd for C20H12ClF6N3O2 (475.1): C, 50.49; H, 2.54; N, 8.83.
Found: C, 50.18; H, 2.72; N, 8.82.
Synthesis 2011, No. 17, 2754–2760 © Thieme Stuttgart · New York

PAPER
Pyrido[2,3-h]quinazolines and 1,7-Phenanthrolines
2759
Anal. Calcd for C20H11F6N3O2 (439.1): C, 54.68; H, 2.52; N, 9.57.
Found: C, 54.65; H, 2.84; N, 9.28.
1H NMR (DMSO-d6–CDCl3): d = 9.90 (dd, J = 2.0, 8.0 Hz, 1 H, H-
10), 9.57–8.97 (m, 4 H, H-5, H-8, OH), 7.81 (dd, J = 4.0, 8.0 Hz, 1
H, H-9), 3.19 (q, J = 7.0 Hz, 2 H, CH2), 2.70 (q, JH,F = 3.0 Hz, 3 H,
CH3), 1.54 (t, 3 H, J = 7.0 Hz, CH2CH3).
1-{2-(4-Chlorophenyl)-4-trifluoromethylpyrido[2,3-h]quinazo-
lin-6-yl}-2,2,2-trifluoroethane-1,1-diol (4g)
Mp 186–187 °C (n-hexane–EtOAc).
IR (KBr): 3352, 3078 cm–1.
Anal. Calcd for C18H14F6N2O2 (404.1): C, 53.47; H, 3.49; N, 6.93.
Found: C, 53.67; H, 3.59; N, 6.53.
1-(2-Ethyl-4-trifluoromethyl-1,7-phenanthrolin-6-yl)-2,2,2-tri-
fluoroethane-1,1-diol (6c)
Mp 135–136 °C (n-hexane–EtOAc).
IR (KBr): 3351 cm–1.
1H NMR (DMSO-d6–CDCl3): d = 9.97 (dd, J = 2.0, 9.0 Hz, 1 H, H-
10), 9.52 (br s, 2 H, OH), 9.35 (dd, J = 2.0, 5.0 Hz, 1 H, H-8), 9.00
(br s, 1 H, H-5), 8.78 (d, J = 9.0 Hz, 2 Harom), 8.07 (dd, J = 5.0, 9.0
Hz, 1 H, H-9), 7.62 (d, J = 9.0 Hz, 2 Harom).
Anal. Calcd for C20H10ClF6N3O2 (473.0): C, 50.70; H, 2.13; N, 8.87.
Found: C, 50.91; H, 2.29; N, 8.50.
1H NMR (CDCl3): d = 9.76 (dd, J = 1.5, 8.5 Hz, 1 H, H-10), 8.93
(dd, J = 1.5, 4.8 Hz, 1 H, H-8), 8.75 (br s, 1 H, H-5), 7.80 (br s, 1 H,
H-3), 7.79 (br s, 2 H, OH), 7.71 (dd, J = 4.8, 8.5 Hz, 1 H, H-9), 3.20
(q, J = 7.5 Hz, 2 H, CH2), 1.53 (t, J = 7.5 Hz, 3 H, CH3).
2,2,2-Trifluoro-1-(4-trifluoromethyl-1,7-phenanthrolin-6-
yl)ethane-1,1-diol (5a)
Mp 133–134 °C (n-hexane–EtOAc).
IR (KBr): 3356 cm–1.
Anal. Calcd for C17H12F6N2O2 (390.1): C, 52.32; H, 3.10; N, 7.18.
Found: C, 52.71; H, 3.16; N, 6.81.
2,2,2-Trifluoro-1-(2-isopropyl-4-trifluoromethyl-1,7-phenan-
throlin-6-yl)ethane-1,1-diol (6d)
Mp 149–150 °C (n-hexane–EtOAc).
IR (KBr): 3348 cm–1.
1H NMR (CD3CN–CDCl3): d = 9.82 (dd, J = 2.0, 8.0 Hz, 1 H, H-
10), 9.38 (d, J = 5.0 Hz, 1 H, H-2), 9.13 (dd, J = 2.0, 4.0 Hz, 1 H,
H-8), 9.00-8.30 (br, 2 H, OH), 8.87 (br s, 1 H, H-5), 8.13 (d, J = 5.0
Hz, 1 H, H-3), 7.90 (dd, J = 4.0, 8.0 Hz, 1 H, H-9).
Anal. Calcd for C15H8F6N2O2 (362.0): C, 49.74; H, 2.23; N, 7.73.
Found: C, 49.55; H, 2.60; N, 7.54.
1H NMR (CDCl3): d = 9.71 (dd, J = 1.6, 8.4 Hz, 1 H, H-10), 8.89
(dd, J = 1.6, 4.4 Hz, 1 H, H-8), 8.73 (br s, 1 H, H-5), 7.90 (br s, 2 H,
OH), 7.82 (br s, 1 H, H-3), 7.66 (dd, J = 4.4, 8.4 Hz, 1 H, H-9), 3.44
(hept, J = 6.9 Hz, 1 H, CH), 1.52 (d, J = 6.9 Hz, 6 H, CH3).
2,2,2-Trifluoro-1-(3-methyl-4-trifluoromethyl-1,7-phenanthro-
lin-6-yl)ethane-1,1-diol (5b)
Mp 185–186 °C (EtOAc).
IR (KBr): 3366 cm–1.
Anal. Calcd for C18H12F6N2O (386.1) (unhydrated form): C, 55.97;
H, 3.13; N, 7.25. Found: C, 56.09; H, 3.38; N, 6.88.
2,2,2-Trifluoro-1-(2-phenyl-4-trifluoromethyl-1,7-phenanthro-
lin-6-yl)ethane-1,1-diol (6e)
Mp 213–214 °C (n-hexane–EtOAc).
IR (KBr): 3346 cm–1.
1H NMR (DMSO-d6–CDCl3): d = 10.07–8.90 (br, 2 H, OH), 9.88
(dd, J = 2.0, 8.0 Hz, 1 H, H-10), 9.33–9.25 (m, 2 H, H-2, H-8), 9.07
(br s, 1 H, H-5), 8.07 (dd, J = 4.0, 8.0 Hz, 1 H, H-9), 2.87 (q,
JH,F = 4.0 Hz, 3 H, CH3).
Anal. Calcd for C16H10F6N2O2 (376.1): C, 51.07; H, 2.68; N, 7.45.
Found: C, 50.73; H, 2.82; N, 7.37.
1H NMR (CDCl3): d = 9.91 (dd, J = 1.6, 8.3 Hz, 1 H, H-10), 9.01
(dd, J = 1.6, 4.4 Hz, 1 H, H-8), 8.82 (br s, 1 H, H-5), 8.41 (br s, 1 H,
H-3), 8.36 (br s, 2 H, OH), 7.81 (dd, J = 4.4, 8.3 Hz, 1 H, H-9),
7.65–7.58 (m, 5 H, C6H5).
Three-Component Condensation Reaction of 2 with Ketones in
the Presence of Ammonia; General Procedure
Anal. Calcd for C21H12F6N2O2 (438.1): C, 57.54; H, 2.76; N, 6.39.
Found: C, 57.27; H, 2.75; N, 5.99.
The appropriate ketone (3.00 or 5.00 mmol) and 28% (w/w) aq NH3
(3.00 or 5.00 mmol) were added to a solution of 2 (354 mg, 1.00
mmol) in MeCN (5 mL), and the mixture was stirred at 50 °C for
24–120 h. In the case of diethyl ketone, the mixture was heated
80 °C in a sealed tube. Evaporation of the solvent in vacuo gave a
crude mixture, which was subjected to column chromatography (sil-
ica gel, n-hexane–EtOAc, 5:1 to 1:1) to give the corresponding 6a–
h and 7.
2,2,2-Trifluoro-1-(7-trifluoromethyl-9,10-dihydro-8H-cyclo-
penta[b][1,7]phenanthrolin-5-yl)ethane-1,1-diol (6f)
Mp 177–178 °C (n-hexane–EtOAc).
IR (KBr): 3349 cm–1.
1H NMR (CDCl3): d = 9.75 (dd, J = 1.5, 8.4 Hz, 1 H, H-1), 8.95 (dd,
J = 1.5, 4.4 Hz, 1 H, H-3), 8.80 (br s, 1 H, H-6), 7.90 (br s, 2 H, OH),
7.74 (dd, J = 4.4, 8.4 Hz, 1 H, H-2), 3.46–3.42 (m, 2 H, ArCH2),
3.32 (t, J = 7.8 Hz, 2 H, ArCH2), 2.32 (quint, J = 7.8 Hz, 2 H,
CH2CH2CH2).
2,2,2-Trifluoro-1-(2-methyl-4-trifluoromethyl-1,7-phenanthro-
lin-6-yl)ethane-1,1-diol (6a)
Mp 142–143 °C (n-hexane–EtOAc).
IR (KBr): 3370 cm–1.
1H NMR (DMSO-d6–CDCl3): d = 9.90 (dd, J = 2.0, 8.0 Hz, 1 H, H-
10), 9.56 (s, 2 H, OH), 9.15 (dd, J = 2.0, 4.0 Hz, 1 H, H-8), 8.92 (br
s, 1 H, H-5), 8.02–7.79 (m, 2 H, H-3, H-9), 2.99 (s, 3 H, CH3).
Anal. Calcd for C18H12F6N2O2 (402.1): C, 53.74; H, 3.01; N, 6.96.
Found: C, 53.64; H, 2.92; N, 6.56.
2,2,2-Trifluoro-1-(7-trifluoromethyl-8,9,10,11-tetrahydroben-
zo[b][1,7]phenanthrolin-5-yl)ethane-1,1-diol (6g)
Mp 149–150 °C (n-hexane–EtOAc).
IR (KBr): 3366 cm–1.
Anal. Calcd for C16H10F6N2O2 (376.1): C, 51.07; H, 2.68; N, 7.45.
Found: C, 51.12; H, 2.92; N, 7.36.
1H NMR (DMSO-d6–CDCl3): d = 9.73 (dd, J = 2.0, 8.0 Hz, 1 H, H-
1), 9.47 (br s, 2 H, OH), 9.17–8.88 (m, 2 H, H-3, H-6), 7.77 (dd,
J = 4.0, 8.0 Hz, 1 H, H-2), 3.50–3.00 (m, 4 H, ArCH2), 2.20–1.79
[m, 4 H, CH2(C2H4)CH2].
1-(2-Ethyl-3-methyl-4-trifluoromethyl-1,7-phenanthrolin-6-
yl)-2,2,2-trifluoroethane-1,1-diol (6b)
Mp 136–137 °C (n-hexane–EtOAc).
IR (KBr): 3336 cm–1.
Synthesis 2011, No. 17, 2754–2760 © Thieme Stuttgart · New York

2760
M. Hinoshita et al.
PAPER
(3) (a) Czuba, W. Rocz. Chem. 1967, 41, 289; Chem. Abstr.
Anal. Calcd for C19H14F6N2O2 (416.1): C, 54.81; H, 3.39; N, 6.73.
Found: C, 55.20; H, 3.37; N, 6.35.
1967, 67, 54056. (b) Tomioka, Y.; Ohkubo, K.; Yamazaki,
M. Chem. Pharm. Bul. 1985, 33, 1360. (c) Ostrowski, S.
Heterocycles 1996, 43, 389. (d) Murashima, T.; Fujita, K.;
Ono, K.; Ogawa, T.; Uno, H.; Ono, N. J. Chem. Soc., Perkin
Trans. 1 1996, 1403. (e) Kumari, T. A.; Reddy, M. S.; Rao,
P. J. Synth. Commun. 2002, 32, 235. (f) Kumari, T. A.; Rao,
P. J. Synth. Commun. 2002, 32, 2261.
2,2,2-Trifluoro-1-(7-trifluoromethyl-9,10,11,12-tetrahydro-8H-
cyclohepta[b][1,7]phenanthrolin-5-yl)ethane-1,1-diol (6h)
Mp 159–160 °C (n-hexane–EtOAc).
IR (KBr): 3361 cm–1.
1H NMR (DMSO-d6–CDCl3): d = 9.78 (dd, J = 2.0, 8.0 Hz, 1 H, H-
1), 9.44 (br s, 2 H, OH), 9.17–8.92 (m, 2 H, H-3, H-6), 7.77 (dd,
J = 4.0, 8.0 Hz, 1 H, H-2), 3.65–3.06 (m, 4 H, ArCH2), 2.14–1.69
[m, 6 H, CH2(C3H6)CH2].
(4) Prado, S.; Michel, S.; Tillequin, F.; Koch, M.; Pfeiffer, B.;
Pierré, A.; Léonce, S.; Colson, P.; Baldeyrou, B.; Lansiaux,
A.; Bailly, C. Bioorg. Med. Chem. 2004, 12, 3943.
(5) (a) Yapi, A. D.; Mustofa, M.; Valentin, A.; Chavignon, O.;
Teulade, J.-C.; Mallie, M.; Chapat, J.-P.; Blache, Y. Chem.
Pharm. Bull. 2000, 48, 1886. (b) Scheibel, L. W.; Adler, A.
Mol. Pharmacol. 1982, 22, 140.
Anal. Calcd for C20H16F6N2O2 (430.1): C, 55.82; H, 3.75; N, 6.51.
Found: C, 56.09; H, 3.85; N, 6.13.
(6) (a) Cuesta, J.; Read, M. A.; Neidle, S. Mini-Rev. Med. Chem.
2003, 3, 11. (b) Mergny, J.-L.; Lacroix, L.; Teulade-Fichou,
M.-P.; Hounsou, C.; Guittat, L.; Hoarau, M.; Arimondo, P.
B.; Vigneron, J.-P.; Lehn, J.-M.; Riou, J.-F.; Garestier, T.;
Hélène, C. Proc. Natl. Acad. Sci. U.S.A. 2001, 98, 3062.
(7) Pedireddi, V. R. Cryst. Growth Des. 2001, 1, 383.
(8) Representative examples: (a) Hojo, M.; Masuda, R.; Okada,
E. Synthesis 1990, 481. (b) Okada, E.; Tone, H.; Tsukushi,
N.; Otsuki, Y.; Takeuchi, H.; Hojo, M. Heterocycles 1997,
45, 339. (c) Okada, E.; Tsukushi, N. Heterocycles 2000, 53,
127. (d) Shibata, D.; Okada, E.; Miyaoku, T.; Molette, J.;
Médebielle, M. Tetrahedron 2009, 65, 6189.
2,2,2-Trifluoro-1-(4¢-trifluoromethylspiro[cyclohexane-1,2¢-
[1,2]dihydropyrido[2,3-h]quinazoline]-6¢-yl)ethanone (7)
Mp 167–168 °C (n-hexane–EtOAc).
IR (KBr): 3382, 2944, 1662 cm–1.
1H NMR (CD3CN): d = 9.16–8.90 (m, 1 H, H-10¢), 8.84–8.53 (m, 1
H, H-8¢), 8.14 (br s, 1 H, H-5¢), 7.63 (dd, J = 4.0, 8.5 Hz, 1 H, H-9¢),
6.77–5.78 (br, 1 H, NH), 2.00–1.43 (m, 10 H, C5H10).
Anal. Calcd for C19H15F6N3O (415.1): C, 54.94; H, 3.64; N, 10.12.
Found: C, 55.28; H, 3.70; N, 9.73.
(9) (a) Okada, E.; Masuda, R.; Hojo, M.; Tone, H.; Gotoh, N.;
Huang, T.-K. Heterocycles 1995, 40, 905. (b) Okada, E.;
Tsukushi, N.; Huang, T.-K.; Tone, H.; Gotoh, N.; Takeuchi,
H.; Hojo, M. Heterocycles 1998, 48, 95. (c) Okada, E.;
Tsukushi, N. Heterocycles 1999, 51, 2471. (d) Okada, E.;
Tsukushi, N. Synthesis 2000, 499.
(10) Shibata, D.; Okada, E.; Hinoshita, M.; Médebielle, M.
Synthesis 2009, 3039.
(11) Reduction of 5-nitroquinoline with Fe/AcOH: Mellor, J. M.;
Merriman, G. D. Steroids 1995, 60, 693.
(12) N,N-Dimethylation of 5-aminoquinoline with MeI/LiNH2:
Feller, C.; Renault, J. Bull. Soc. Chim. Fr. 1973, 1112.
(13) Review: Marco-Contelles, J.; Pérez-Mayoral, E.; Samadi,
A.; Carreiras, M. D.; Soriano, E. Chem. Rev. 2009, 109,
2652.
References
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(h) Burger, K.; Wucherpfennig, U.; Brunner, E. Adv.
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Synthesis 2011, No. 17, 2754–2760 © Thieme Stuttgart · New York