A facile one-pot synthesis of 2-substituted-3-aminoquinolines: Preparation of benzo[b]naphthyridine-3-carbonitriles

Article abstract of DOI:10.1016/j.tet.2004.02.012

A facile one-pot synthesis of 3-aminoquinolines from ortho- aminobenzaldehydes was developed. Ethyl 6,7-dimethoxy-3-aminoquinoline-2- carboxylate, a key intermediate for the preparation of a 4-anilino-benzo[b][1,5] -naphthyridine-3-carbonitrile, was efficiently prepared by this method. Synthetic routes to 4-anilino-benzo[b][1,5]-naphthyridine-3-carbonitrile and 4-anilino-benzo[b][1,8]-naphthyridine-3-carbonitrile are described.

Full text of DOI:10.1016/j.tet.2004.02.012

Tetrahedron 60 (2004) 2937–2942
A facile one-pot synthesis of 2-substituted-3-aminoquinolines:
preparation of benzo[b]naphthyridine-3-carbonitriles
*
Yanong D. Wang, Diane H. Boschelli, Steven Johnson and Erick Honores
Chemical and Screening Sciences, Wyeth Research, 401 N. Middletown Road 222-3034, Pearl River, NY 10965, USA
Received 8 January 2004; revised 8 February 2004; accepted 8 February 2004
Abstract—A facile one-pot synthesis of 3-aminoquinolines from ortho-aminobenzaldehydes was developed. Ethyl 6,7-dimethoxy-3-
aminoquinoline-2-carboxylate, a key intermediate for the preparation of a 4-anilino-benzo[b][1,5]-naphthyridine-3-carbonitrile, was
efficiently prepared by this method. Synthetic routes to 4-anilino-benzo[b][1,5]-naphthyridine-3-carbonitrile and 4-anilino-benzo[b][1,8]-
naphthyridine-3-carbonitrile are described
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
and coupling reaction of 11 with 2,4-dichloro-5-methoxy-
aniline gave the final product 4.
Protein tyrosine kinases (PTKS), including Src,1 are key
elements in signal transduction pathways regulating a
number of cellular functions such as cell growth and
differentiation. The activation and over-expression of Src
has been implicated in a number of diseases, including
cancer.2 Small molecule inhibitors of Src activity could be
beneficial for the treatment of various diseases. Several
classes of Src kinase inhibitors have been reported in the
literature.3
We previously reported that 4-anilino-3-quinolinecarbo-
nitriles,4,5 1 and 2, were potent inhibitors of Src kinase
activity. It was subsequently shown that 4-anilino-benzo[g]-
quinoline-3-carbonitrile 3,6 which has a phenyl ring fused to
the 3-quinolinecarbonitrile, also inhibited Src kinase
activity. Aza analogs of 3-quinolinecarbonitriles (1 and 2),
which have [1,7], [1,5] or [1,8]-naphthyridine bicyclic
cores, were also reported to be inhibitors of PTKs.7
Compounds 4 and 5, which have a 5-aza/10-aza tricyclic
scaffold, were therefore designed as potential Src inhibitors.
To synthesize 4-anilino-benzo[b][1,5]-naphthyridine-3-
carbonitrile 5 using an analogous approach to the one
described above, the major challenge would be the
preparation of 3-amino-2-quinolinecarboxylate
C
2. Results and discussion
(Scheme 2). At the inception of our work, there was only
one report of the synthesis of a 3-amino-2-quinoline-
carboxylate in the literature.
Treatment of 6-nitroveratraldehyde with methyl cyano-
acetate followed by reduction provided 2-aminoquinoline 8
(Scheme 1). Reaction of 8 with N,N-dimethylformamide
dimethyl acetal (DMF-DMA) followed by addition of the
anion of acetonitrile gave 10. Subsequent chlorination of 10
Westphal et al. disclosed8 that the condensation of ortho-
aminobenzaldehyde with 1-(2-ethoxycarbonyl-2-oxoethyl)-
pyridinium bromide D, prepared from pyridine and ethyl
2-bromopyruvate, gave 3-pyridino-quinoline E (Scheme 3).
Upon treatment with pyrrolidine, E was converted to
3-aminoquinoline F. A major drawback of this approach
Keywords: 3-Aminoquinolines; Benzo[b]naphthyridine-3-carbonitriles.
*
Corresponding author. Tel.: þ1-8456025253; fax: þ1-8456025561;
e-mail address: wangd@wyeth.com
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.02.012

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Y. D. Wang et al. / Tetrahedron 60 (2004) 2937–2942
Scheme 1.
Scheme 2.
Scheme 3.
was that the coupling reaction of D with ortho-amino-
benzaldehyde gave a poor yield (,30%) of E. It did,
however, offer an efficient and concise approach to
functionalized 3-aminoquinolines from readily accessible
starting materials.
improve the existing procedure. We found that the poor
reproducibility in pyridinium formation and the low yield in
its subsequent condensation with ortho-aminobenzalde-
hydes were mainly due to the hydroscopicity and instability
of compounds D and E when exposed to the atmosphere. A
one-pot procedure, that did not require separation and
purification of intermediates D and E, was therefore
This prompted us to investigate possible modifications to
Scheme 4.

Y. D. Wang et al. / Tetrahedron 60 (2004) 2937–2942
2939
developed. In order to improve the overall yield of this one-
pot approach, we also optimized the reaction conditions,
including temperature, time and the ratio of reagents and
substrates. Under the optimal reaction conditions, 13a
(Scheme 4) was obtained in 90% overall yield from ortho-
aminobenzaldehyde. This method also provided satisfactory
yields for the condensations of various substituted ortho-
aminobenzaldehydes (13b-13e and 13g, Scheme 4). By
preparing other 2-substituted-3-aminoquinolines (13f-13h,
Scheme 4), the versatility of this methodology was
demonstrated. It is worthwhile to note that the coupling
reactions of the pyridinium salt with ortho-aminobenzalde-
hydes, when the R group is Me or Ph, were somewhat
sluggish. We found that the addition of a catalytic amount of
a relatively strong base such as 4-(dimethylamino)pyridine
facilitated the reaction.
NMR spectra were recorded on a NT-300 WB spectrometer.
Electrospray (ES) mass spectra were recorded on a Microma
Platform mass spectrometer. Flash chromatography was
performed with Baker 40 mM silica gel. Reactions were
generally carried out under an inert atmosphere of
nitrogen.
3.2. Compounds 7-11 and 4
3.2.1. Methyl (E)-2-cyano-3-(4,5-dimethoxy-2-nitro-
phenyl)-2-propenoate (7). To a mixture of 6-nitro-
veratraldehyde (80%) (7.00 g, 33.2 mmol) and methyl
cyanoacetate (3.4 mL, 38.4 mmol) in methanol (170 mL)
was added piperidine (0.70 mL). The reaction mixture was
stirred at room temperature for 1 h. The resultant solid was
collected by filtration washing with methanol and diethyl
ether to provide 7 (7.57 g, 78%) as a pale yellow solid; mp
1
With ethyl 3-aminoquinoline-2-carboxylate 13b in hand, we
embarked on converting it to the target 4-anilino-benzo-
[b][1,5]-naphthyridine-3-carbonitrile 5 (Scheme 5). Treat-
ment of 13b with DMF-DMA gave amidine 14. Reaction of
14 with the anion of acetonitrile followed by chlorination
with phosphorus oxychloride provided 15. Coupling of 15
with 2,4-dichloro-5-methoxyaniline gave target compound
5.
162–164 8C; H NMR (d, ppm, DMSO-d6): 3.90 (s, 3H),
3.94 (s, 3H), 3.96 (s, 3H), 7.56 (s, 1H), 7.83 (s, 1H), 8.77 (s,
1H); m/z (ES) (MH)2¼292.1. Anal. Calcd for C13H12N2O6:
C, 53.43; H, 4.14; N, 9.59. Found: C, 53.03; H, 4.02; N,
9.59.
3.2.2. Methyl 2-amino-6,7-dimethoxy-3-quinolinecar-
boxylate (8). A mixture of 7 (7.00 g, 24.0 mmol) and iron
(5.00 g, 89.6 mmol) in acetic acid (100 mL) was heated at
reflux for 10 min. The reaction mixture was cooled slightly
and the solids were removed by filtration, washing with
ethyl acetate. The filtrate was concentrated in vacuo and the
residue was partitioned between ethyl acetate and aqueous
sodium bicarbonate. The organic layer was dried over
magnesium sulfate, filtered and concentrated in vacuo.
Trituration of the residue with diethyl ether provided 8
(652 mg, 10%) as a pale yellow solid. Acidification of the
aqueous layer with concentrated hydrochloric acid caused
additional product to precipitate out. This material was
collected by filtration, washed with water and ethyl acetate
to provide an additional amount of 8 (1.57 g, 25%); mp
1
227–229 8C; H NMR (d, ppm, DMSO-d6): 3.81 (s, 3H),
3.87 (s, 3H), 3.88 (s, 3H), 6.89 (s, 1H), 6.95 (br s, 2H), 7.27
(s, 1H), 8.59 (s, 1H); m/z (ES) (MH)þ¼263.1. Anal. Calcd
for C13H14N2O4: C, 59.54; H, 5.38; N, 10.68. Found: C,
59.56; H, 5.46; N, 10.55.
Scheme 5.
3.2.3. Methyl 2-{[(E)-(dimethylamino)methylidene]-
amino}-6,7-dimethoxy-3-quinoline-carboxylate (9).
A
mixture of 8 (3.6 g, 13.0 mmol), N,N-dimethylformamide
dimethyl acetal (4.1 mL, 31.0 mmol) and p-toluenesulfonic
acid (40 mg) in toluene (60 mL) was heated at reflux for 2 h.
The reaction mixture was cooled to room temperature and
the solid was collected by filtration to provide 9 (737 mg,
18%) as an off-white solid. Concentration of the filtrate
provided an additional 2.86 g (70%) of 9; mp 166–168 8C;
1H NMR (d, ppm, DMSO-d6): 3.00 (s, 3H), 3.12 (s, 3H),
3.81 (s, 3H), 3.85 (s, 3H), 3.90 (s, 3H), 7.14 (s, 1H), 7.29 (s,
1H), 8.20 (s, 1H), 8.50 (s, 1H); m/z (ES) (MH)þ¼318.1.
Anal. Calcd for C16H19N3O4: C, 60.56; H, 6.03; N, 13.24.
Found: C, 60.63; H, 6.08; N, 13.32.
In summary, we present here an efficient one-pot synthesis
of 2-substituted-3-aminoquinolines from ortho-amino-
benzaldehydes. We demonstrated that this method can
potentially be utilized for the preparation of other
3-aminoquinolines with different functional groups at C-2.
In addition, first synthetic routes to a benzo[b][1,5]-
naphthyridine-3-carbonitrile and a benzo[b][1,8]-naphthyri-
dine-3-carbonitrile were described. The activities of target
molecules 4 and 5 will be disclosed elsewhere.
3. Experimental
3.1. General
3.2.4. 4-Hydroxy-7,8-dimethoxybenzo[b][1,8]-naphthyr-
idine-3-carbonitrile (10). To a 278 8C solution of n-butyl
lithium (9.0 mL of a 2.5 M solution, 22.5 mmol) in
tetrahydrofuran (40 mL) was added acetonitrile (1.3 mL,
Melting points were determined in open capillary tubes on a
1
Meltemp melting point apparatus and are uncorrected. H

2940
Y. D. Wang et al. / Tetrahedron 60 (2004) 2937–2942
24.9 mmol). After stirring for 15 min, a solution of 9
(2.86 g, 9.0 mmol) in tetrahydrofuran (100 mL) was added
dropwise over 30 min. The mixture was stirred at 278 8C
for 30 min then allowed to come to room temperature. The
reaction mixture was cooled to 278 8C and acetic acid
(3 mL) was added. The reaction mixture was allowed to
warm to room temperature. The solids were collected by
filtration washing with water, methanol, and ethyl acetate to
provide 10 (1.11 g, 44%) as a light yellow solid; mp
.300 8C; 1H NMR (d, ppm, DMSO-d6): 3.93 (s, 3H), 4.00
(s, 3H), 7.29 (s, 1H), 7.60 (s, 1H), 8.68 (s, 1H), 8.97 (s, 1H);
m/z (ES) (MH)þ¼281.9. Anal. Calcd for C15H11N3O3
20.65 H2O: C, 61.49; H, 4.23; N, 14.34. Found: C, 61.40;
H, 4.40; N, 14.70.
graphed (ethyl acetate/hexanes 1:3) to give 13a as a yellow
1
solid (762 mg, 90%); mp 148–150 8C; H NMR (d, ppm,
DMSO-d6): 1.38 (t, J¼5 Hz, 3H), 4.40 (q, J¼5 Hz, 2H),
6.42 (s, 2H), 7.41 (dt, J¼5, 1 Hz, 1H), 7.47 (dt, J¼5, 1 Hz,
1H), 7.51 (s, 1H), 7.67 (d, J¼5 Hz, 1H), 7.86 (d, J¼5 Hz,
1H); m/z (ES) (MH)þ¼217.1. Anal. Calcd for C12H12N2O2
20.10H2O: C, 66.10; H, 5.62; N, 12.85. Found: C, 65.82; H,
5.50; N, 12.74.
3.3.2. Ethyl 3-amino-6,7-dimethoxy-2-quinolinecar-
boxylate (13b). Following the route used to prepare 13a,
13b was obtained from 2-amino-4,5-dimethoxybenzalde-
hyde (1.0 g, 4.74 mmol) as a yellow solid (1.04 g, 79%); mp
168–170 8C; 1H NMR (d, ppm, DMSO-d6): 1.35 (t,
J¼5 Hz, 3H), 3.32 (s, 6H), 4.35 (q, J¼5 Hz, 2H), 6.31 (s,
br, 2H), 7.00 (s, 1H), 7.16 (s, 1H), 7.40 (s, 1H); m/z (ES)
(MH)þ¼277.2. Anal. Calcd for C14H16N2O4 20.10 H2O:
C, 60.46; H, 5.85; N, 10.08. Found: C, 60.20; H, 6.00; N,
9.91.
3.2.5. 4-Chloro-7,8-dimethoxybenzo[b][1,8]-naphthyri-
dine-3-carbonitrile (11). A mixture of 10 (500 mg,
1.8 mmol) and phosphorous oxychloride (5 mL) was heated
at reflux for 1 h. The reaction mixture was cooled to room
temperature and hexane was added. The resultant solid was
collected by filtration washing with hexane, water, methanol
and ethyl acetate to provide 11 (258 mg, 49%) as a brown
solid; mp .300 8C; 1H NMR (d, ppm, DMSO-d6): 4.01 (s,
3H), 4.07 (s, 3H), 7.58 (s, 1H), 7.77 (s, 1H), 9.27 (s, 1H),
9.34 (s, 1H); m/z (ES) (MH)þ¼299.9. Anal. Calcd for
C15H10ClN3O2 20.40 H2O: C, 58.70; H, 3.55; N, 13.69.
Found: C, 58.85; H, 3.33; N, 13.97.
2-Amino-4,5-dimethoxybenzaldehyde was prepared as
follows: A mixture of 3,4-dimethoxy-6-nitrobenzaldehyde
(2.0 g, 9,47 mmol) and 10% Pd–C (200 mg) in ethanol
(50 mL) was hydrogenated at 40 psi for 2 h. The resulting
suspension was filtered and washed with ethanol. The
filtrate was used directly in the next step.
3.3.3. Ethyl 3-amino-6-chloro-2-quinolinecarboxylate
(13c). Following the route used to prepare 13a, 13c was
obtained from 2-amino-5-chlorobenzaldehyde (500 mg,
3.21 mmol) as a yellow solid (385 mg, 48%): mp 151–
153 8C; 1H NMR (d, ppm, DMSO-d6): 1.37 (t, J¼5 Hz, 3H),
4.41 (q, J¼5 Hz, 2H), 6.58 (s, 2H), 7.36 (dt, J¼7, 2 Hz, 1H),
7.46 (s, 1H), 7.82 (d, J¼2 Hz, 1H), 7.85 (d, J¼7 Hz, 1H);
m/z (ES) (MH)þ¼251.1. Anal. Calcd for C12H11ClN2O2
20.1 C4H8O2: C, 57.39; H, 4.57; N, 10.80. Found: C, 57.35;
H, 4.33; N, 10.53.
3.2.6. 4-(2,4-Dichloro-5-methoxyanilino)-7,8-dimethoxy-
benzo[b][1,8]naphthyridine-3-carbonitrile (4). A mixture
of 11 (150 mg, 0.50 mmol), 2,4-dichloro-5-methoxyaniline
(160 mg, 0.83 mmol) and pyridine hydrochloride (70 mg,
0.60 mmol) in 2-ethoxyethanol (15 mL) was heated at reflux
for 25 min. The resultant black solution was cooled to room
temperature and partitioned between ethyl acetate and
saturated aqueous sodium bicarbonate. The organic layer
was dried over magnesium sulfate, filtered and concentrated
in vacuo to provide 143 mg of a 10:1 mixture of 4 and 10.
This material was dissolved in ethyl acetate and washed
with a solution of saturated aqueous sodium bicarbonate and
sodium hydroxide (pH 11) to remove 10. The organic layer
was dried over magnesium sulfate, filtered and reduced in
vacuo to about 10 mL. The solids were collected by
filtration washing with diethyl ether to provide 4 (86 mg,
3.3.4. Ethyl 3-amino-7-chloro-2-quinolinecarboxylate
(13d). Following the route used to prepare 13a, 13d was
obtained from 2-amino-4-chlorobenzaldehyde9 (500 mg,
3.21 mmol) as a yellow solid (71%); mp 128–130 8C;
1H NMR (d, ppm, DMSO-d6): 1.37 (t, J¼5 Hz, 3H), 4.40
(q, J¼5 Hz, 2H), 6.51 (s, 2H), 7.48 (dt, J¼7, 2 Hz, 1H),
7.55 (s, 1H), 7.74 (d, J¼7 Hz, 1H), 7.90 (d, J¼2 Hz,
1H); m/z (ES) (MH)þ¼251.0. Anal. Calcd for
C12H11ClN2O2: C, 57.50; H, 4.42; N, 11.17. Found: C,
57.38; H, 4.22; N, 11.05.
1
38%) as a bright orange solid; mp .290 8C; H NMR (d,
ppm, DMSO-d6): 3.82 (s, 3H), 3.92 (s, 3H), 4.00 (s, 3H),
6.78 (s, 1H), 7.28 (s, 1H), 7.47 (s, 1H), 7.62 (s, 1H), 8.28 (s,
1H), 9.19 (s, 1H); m/z (ES) (MH)þ¼455.0. Anal. Calcd for
C22H16Cl2N4O3: C, 58.04; H, 3.54; N, 12.31. Found: C,
57.86; H, 3.48; N, 12.30.
3.3.5. Ethyl 3-amino-6,8-dibromo-2-quinolinecarboxyl-
ate (13e). Following the route used to prepare 13a, 13e
was obtained from 2-amino-3,5-dibromobenzaldehyde
(896 mg, 3.21 mmol) as a yellow solid (470 mg, 39%);
mp 143–145 8C; 1H NMR (d, ppm, DMSO-d6): 1.36
(t, J¼5 Hz, 3H); 4.41 (q, J¼5 Hz, 2H), 6.71 (s, br, 2H),
7.48 (s, 1H), 7.88 (d, J¼2 Hz, 1H), 8.03 (d, J¼2 Hz, 1H);
(m/z (ES) (MH)þ¼374.9. Anal. Calcd for C12H10Br2N2O2:
C, 38.53; H, 2.53; N, 7.49. Found: C, 38.22; H, 2.53; N,
7.30.
3.3. Compounds 13a-13h
3.3.1. Ethyl 3-amino-2-quinolinecarboxylate (13a). To a
mixture of pyridine (342 mg, 4.34 mol) and ethanol (12 mL)
was added ethyl 2-bromopyruvate (846 mg, 4.34 mmol) in
ethanol (8 mL) dropwise over 20 min. The resulting mixture
was heated at 60–70 8C for one hour and cooled to room
temperature.
ortho-Aminobenzaldehyde
(500 mg,
4.13 mmol) and pyridine (0.80 mL) were added. After
heating at reflux for 5 h, pyrrolidine (698 mg, 9.83 mmol)
was added. The resulting mixture was heated for an
additional 2 h and concentrated. The residue was chromato-
3.3.6. 2-Phenyl-quinoline-3-ylamine (13f). A mixture of
1-phenacylpyridinium bromide (1.20 g, 4.34 mmol), ortho-
aminobenzaldehyde (0.5 g, 4.13 mmol), pyridine (0.2 mL)

Y. D. Wang et al. / Tetrahedron 60 (2004) 2937–2942
2941
and DMAP (catalytic amount) in ethanol was heated at
reflux for 48 h. The reaction mixture was cooled to room
temperature and pyrrolidine (0.82 mL, 9.83 mmol) was
added. After heating at reflux overnight, the resulting
mixture was concentrated. The residue was partitioned
between saturated aqueous sodium bicarbonate and
methylene chloride. The combined organics were dried
over sodium sulfate, concentrated and chromatographed
(ethyl acetate/hexanes 1:3) to give 13f (588 mg, 65%) as a
The resulting mixture was stirred at room temperature
overnight and concentrated. The residue was dissolved in
tetrahydrofuran (50 mL) and a few drops of conc.
hydrochloric acid were added. The reaction mixture was
heated to 70 8C, stirred for 2 h and concentrated. The solid
residue was slurried in water (30 mL), filtered and washed
with water and ether to provide 7,8-dimethoxy-4-hydroxy-
benzo[b][1,5]naphthyridine-3-carbonitrile (525 mg, 58%)
as an off-white solid that was used as it is in next step;
1
yellow solid; mp 100–101 8C; H NMR (d, ppm, DMSO-
d6): 5.25 (s, br, 2H), 7.36–7.40 (m, 3H), 7.47–7.55 (m, 3H),
7.64 (d, J¼6 Hz, 1H), 7.73 (dd, J¼1, 6 Hz, 2H), 7.79 (d,
J¼5 Hz, 1H); m/z (ES) (MH)þ¼221.1. Anal. Calcd for
C15H12N2 20.05 H2O C, 81.45; H, 5.50; N, 12.67. Found:
C, 81.29; H, 5.35; N, 12.69.
A mixture of 7,8-dimethoxy-4-hydroxy-benzo[b][1,5]-
naphthyridine-3-carbonitrile (428 mg, 1.52 mmol) and
phosphorous oxychloride (4.94 g, 32.2 mmol) was heated
at reflux for 1 h and concentrated. The residue was carefully
neutralized with saturated sodium bicarbonate with cooling
on an ice-bath, filtered and washed thoroughly with water to
give 15 (454 mg, 88%) as a light brown solid; mp .340 8C;
1H NMR (d, ppm, DMSO-d6): 4.02 (s, 3H), 4.07 (s, 3H),
7.56 (s, 1H), 7.57 (s, 1H), 9.04 (s, 1H), 9.18 (s, 1H); m/z (ES)
(MH)þ¼300.1. Anal. Calcd for C15H10ClN3O2 22.0 HCl
48.34; H, 3.24; N, 11.08. Found: C, 48.57; H, 3.42; N, 10.75.
3.3.7. 6,7-Dimethoxy-2-phenyl-quinoline-3-ylamine
(13g). Following the route used to prepare 13f, 13g was
obtained from 2-amino-4,5-dimethoxybenzaldehyde (1.0 g,
4.75 mmol) as a yellow solid (996 mg, 75%); mp 148–
149 8C; 1H NMR (d, ppm, DMSO-d6): 3.84 (s, 3H), 3.87 (s,
3H), 4.98 (s, br, 2H), 7.03 (s, 1H), 7.19 (s, 1H), 7.32 (s, 1H),
7.41–7.52 (m, 3H), 7.72–7.74 (m, 2H); m/z (ES)
(MH)þ¼281.1. Anal. Calcd for C17H16N2O2 C, 72.84; H,
5.75; N, 9.99. Found: C, 72.44; H, 5.56; N, 9.66.
3.4.3. 4-(2,4-Dichloro-5-methoxyanilino)-7,8-dimethoxy-
benzo[b][1,5]naphthyridine-3-carbonitrile (5). A mixture
of 15 (100 mg, 0.334 mmol), 2,4-dichloro-5-methoxy-
aniline (67 mg, 0.351 mmol) and pyridine-HCl (43 mg,
0.368 mmol) in 2-ethoxyethanol (2.2 mL) was heated at
100 8C for 5 h. The resultant reaction mixture was diluted
with saturated sodium bicarbonate and was allowed to stir
one hour at room temperature. The suspension was filtered
and washed thoroughly with water, followed by a minimum
amount of methanol and hexanes to give 5 (75 mg, 50%) as
a light yellow solid; mp .360 8C; 1H NMR (d, ppm,
DMSO-d6): 3.76 (s, 3H), 3.89 (s, 3H), 3.95 (s, 3H), 6.69 (s,
1H), 7.14 (s, 1H), 7.32 (s, 2H), 7.98 (s, 1H), 8.20 (s, 1H); m/z
(ES) (MH)þ¼455.1. Anal. Calcd for C22H16Cl2N4O3 20.5
H2O C, 56.91; H, 3.67; N, 12.07. Found: C, 56.74; H, 3.70;
N, 11.77.
3.3.8. 2-Methyl-quinoline-3-ylamine (13h). Following the
route used to prepare 13f, 13h was obtained from ortho-
aminobenzaldehyde (388 mg, 3.21 mmol) and N-acetonyl-
pyridinium bromide (762 mg, 3.53 mmol) as a off-white
1
solid (262 mg, 52%): mp 142–143 8C; H NMR (d, ppm,
DMSO-d6): 2.48 (s, 3H), 5.39 (s, br, 2H), 7.16 (s, 1H),
7.27–7.34 (m, 2H), 7.57 (dd, J¼6, 3 Hz, 1H), 7.70 (dd,
J¼6, 3 Hz, 1H); m/z (ES) (MH)þ¼159.0. Anal. Calcd for
C10H10N2 20.1 CH2Cl2 C, 71.31; H, 6.06; N, 16.39. Found:
C, 71.33; H, 5.67; N, 16.28.
3.4. Compounds 13-15 and 5
3.4.1. Ethyl 3-{([(E)-(dimethylamino)methylidene]-
amino}-6,7-dimethoxy-2-quinoline-carboxylate (14). A
mixture of 13b (1.0 g, 3.61 mmol) and N,N-dimethylforma-
mide dimethyl acetal (1.34 g, 9.04 mmol) in toluene
(30 mL) was heated at 80 8C for 5 h and concentrated.
The solid residue was slurried in hexanes, filtered and
washed with hexanes to give 14 (1.22 g, 100%) as an off-
white solid; mp 135–140 8C; 1H NMR (d, ppm, DMSO-d6):
1.31 (t, J¼5 Hz, 3H), 2.93 (s, 3H), 3.05 (s, 3H), 4.31 (q,
J¼5 Hz, 2H), 3.89 (s, 6H), 7.16 (s, 1H), 7.29 (s, 1H), 7.69 (s,
1H), 7.89 (s, 1H); m/z (ES) (MH)þ¼332.2. Anal. Calcd for
C17H21N3O4 C, 61.62; H, 6.39; N, 12.68. Found: C, 61.78;
H, 6.37; N, 12.65.
Acknowledgements
We thank the members of the Wyeth Discovery Analytical
Chemistry Department for the spectral data and elemental
analyses. We also thank Drs. Dennis Powell and Tarek
Mansour for their support of this work.
References and notes
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