Synthesis of novel 2,3-dihydro-1,4-dioxino[2,3-g]quinoline derivatives as potential antitumor agents

Article abstract of DOI:10.1016/j.bmc.2003.12.024

New dioxinoquinolines (1-8) have been synthesized and their antiproliferative properties have been tested against several cell lines. The treatment of the 6-acetamido-2,3-dihydro-1,4-benzodioxine (10) with phosphorous oxychloride in the presence of DMF le

Full text of DOI:10.1016/j.bmc.2003.12.024

Bioorganic & Medicinal Chemistry 12 (2004) 949–956
Synthesis of novel 2,3-dihydro-1,4-dioxino[2,3-g]quinoline
derivatives as potential antitumor agents
M. T. Vazquez, M. Romero and M. D. Pujol*
´
Laboratori de Quımica Farmaceutica, Unitat associada al CSIC, Facultat de Farmacia, Universitat de Barcelona,
`
`
Av. Diagonal 643, E-08028-Barcelona, Spain
Received 25 July 2003;accepted 16 December 2003
Abstract—New dioxinoquinolines (1–8) have been synthesized and their antiproliferative properties have been tested against several
cell lines. The treatment of the 6-acetamido-2,3-dihydro-1,4-benzodioxine (10) with phosphorous oxychloride in the presence of
DMF leads to a mixture of linear and angular tricyclic compounds. The key intermediates were modified and cyclized giving the
corresponding dioxinoquinolines. In general, these compounds have a moderate citotoxycity.
# 2003 Elsevier Ltd. All rights reserved.
Figure 1. Analogue compounds of camptothecin.
1. Introduction
Given their great biological properties, compounds
containing the quinoline system have been the subject of
many synthetic studies. In a general program, we syn-
thesize antitumor agents related to natural products
(camptothecin, ellipticine and podophyllotoxin, among
others). Our aim is to develop series of synthetic mole-
cules which are more accessible and more amenable to
optimisation through analogue synthesis. This paper
describes the preparation of quinolines fused with a 1,4-
dioxane group at positions 5–6 or 6–7 of the quinoline
ring (Fig. 1). The new linear or angular tetracyclic
compounds can be considered simplified camptothecin
analogues having certain modifications in the lactone
ring, and suppression of C, and D rings. These struc-
Several polycyclic analogues of natural or semi-syn-
thetic antitumor agents are well known, and have
attracted considerable interest because of their significant
anticancer activity, due to the inhibition of topoisomerase
I or topoisomerase II, or to intercalation on DNA.1ꢀ5
Structure–activity studies on antitumor compounds rela-
ted to 1,4-benzodioxine derivatives show that fused 1,4-
dioxine systems retained significant activity.6
* Corresponding author. Tel.: +34-93-402-4534;+34-93-403-5941;
e-mail: mdpujol@farmacia.far.ub.es
0968-0896/$ - see front matter # 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2003.12.024

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950
Scheme 1. Reagents and conditions: i (CH3CO)2O, 140 ꢁC;ii POCl 3/DMF, 90 ꢁC.
tures were designed by pharmacomodulation of camp-
tothecin in order to simplify the molecule and produce
an amelioration of its properties, thus the results may
provide key data about the critical structure necessary
for the activity of related agents. These compounds are
weakly basic and possess, or not, an electrophilic centre
on the ring D. Camptothecin inhibits topoisomerase I
by stabilizing a covalent enzyme–DNA complex,7 but
does not affect isolated enzyme or isolated DNA,
suggesting that a drug binding site is formed when the
complex topisomerase I-DNA is formed.8 Several stud-
ies on camptothecin derivatives show that the lactone
ring, as an electrophilic group, is the critical region for
the antitumor activity.9 The clinical application of
camptothecin in the treatment of cancer has been
limited by severe toxic side effects during the administr-
ation of the drug, and by solubility problems.10
and J=0.5 Hz) at 7.38 and 7.49 ppm (attributed to H-5
and H-6). In contrast, the H-9, and H-10 of compound
11 appeared as two doublets (J=0.5 Hz).
To improve the yields and scope of the synthesis of
these tricyclic compounds, we tested a variety of condi-
tions for the POCl3–DMF reactions and found that
regioselectivity is governed by temperature and addition
of the POCl3 reagent. A temperature higher than 90 ꢁC
favoured the formation of the angular isomer 12. In our
experience, the linear isomer 11 is most favoured when
the POCl3 was added slowly and the temperature did
not exceed 90 ꢁC.
Transformation of 11 and 12 to the aminoalcohols 15 or
16, respectively, was attempted in two ways: reduction
of the aldehyde group followed by 2-chloro substitu-
tion, or firstly substitution followed by reduction of the
aminocarbaldehyde intermediate;the last strategy is pre-
ferable. Substitution of the 2-chloro group by methyl-
amine gave 87% (compound 13) and 97% yield
(compound 14), whereas the same substitution of the
corresponding chloro-alcohols gave the desired com-
pounds after long reaction times (14 days). This result is
understandable;since the aldehyde group is more activat-
ing than the hydroxy-methyl group to nucleophilic sub-
stitution of the adjacent chlorine, moreover alcohol 15 has
solubility troubles which decreased the yield of reaction.
2. Chemistry
New potential anticancer agents (1–8) were synthesised
from aniline 9 by a straightforward high-yield process
(Scheme 1). Acylation of the 6-amino-2,3-dihydro-1,4-
benzodioxine with acetic anhydride in the presence of
triethylamine afforded the corresponding acetamide 10.
The key intermediates 11 and 12 were obtained from 10
by bis-formylation at the side chain under Vilsmeier
conditions.11ꢀ15
Finally, we examined the cyclization of the secondary
amines to tetracyclic systems. Acylation of amino-
alcohols 15–16 with dimethyl carbonate and butyl
lithium afforded the carbamate 2 in low yield (24%),
and the carbamate 6 (48%) respectively, while cycli-
zation using formaldehyde16 gave amino-ethers 1 in
45%, and 5 in 57% yield, respectively (Scheme 2). The
analogous compounds 4 and 8 were obtained from the
corresponding diamines 19–20, using the same formal-
dehyde methodology.
The dialdehyde obtained by heating the acetamide 10
with phosphorous oxychloride in DMF at 80–90 ꢁC,
was quickly cyclized in situ to give 11 in good yield
(71%). In this case, two cyclization pathways were pos-
sible;linear ( 11) and angular (12) tricyclic compounds
were obtained. The best conditions of the Vilsmeier
reaction were achieved in an one-pot procedure and
provided compound 11 in 71% yield, whereas the
phenanthrene analogue 12 was obtained in only 5%,
which was attributed to steric effects. The structures of
1
11, and 12 were confirmed by H and 13C NMR. The
The low yields obtained in the preparation of com-
pounds 1, 2, 5, and 6, is possible due to competing
reaction of the nitrogen atom of the pyridine ring.
structural assignment of 12 was confirmed by the
appearance of two aromatic double doublets (J=9.2

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M. T. Vazquez et al. / Bioorg. Med. Chem. 12 (2004) 949–956
951
Scheme 2. Reagents and conditions: iii CH3NH2 (40%)/MeOH, 90 ꢁC. iv. NaBH4/MeOH. v. HCHO/APTS/toluene reflux. vi. NaOMe/(CH3O)2CO,
100 ꢁC.
The oxopyrimidoquinolines 3 and 7 were synthesized in
acceptable yields by reacting the corresponding diami-
nocompounds 19 or 20 with dimethyl carbonate in the
presence of butyl lithium.
NMR, 13C NMR. All new compounds gave satisfactory
analysis and spectral data.
Further studies on the chemical behaviour and on
the biological activities of these derivatives are in
progress.
The purity of the products was checked by TLC, IR, 1H
Table 1. In vitro anticancer activity of the compounds 1–8 (expressed as mean log GI50
)
Compounds
Cell line
1
2
3
4
5
6
7
8
Leukemia (RPMI-8226)
Non small cell lung cancer (EKVX)
Cancer colon (KM12)
CNS cancer (SF-268)
Renal cancer (A498)
Breast cancer (HS-578T)
ꢀ5.65
ꢀ4.41
ꢀ4.36
ꢀ4.87
ꢀ4.00
ꢀ7.95
ꢀ4.00
ꢀ5.87
ꢀ4.23
ꢀ4.57
ꢀ4.73
ꢀ5.78
ꢀ4.00
ꢀ4.25
ꢀ4.12
ꢀ5.23
ꢀ4.00
ꢀ4.32
ꢀ4.00
ꢀ4.56
ꢀ4.67
ꢀ4.00
ꢀ4.00
ꢀ5.22
ꢀ4.21
ꢀ4.00
ꢀ4.00
ꢀ4.00
ꢀ4.00
ꢀ5.55
ꢀ6.02
ꢀ5.21
ꢀ5.43
ꢀ4.65
ꢀ4.32
ꢀ4.67
ꢀ4.00
ꢀ4.12
ꢀ4.05
ꢀ4.00
ꢀ4.00
ꢀ4.56
ꢀ4.48
ꢀ4.00
ꢀ4.45
ꢀ4.00
ꢀ5.43
ꢀ4.00

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M. T. Vazquez et al. / Bioorg. Med. Chem. 12 (2004) 949–956
952
3. Pharmacological results
resulting organic layer was dried, filtered and con-
centrated affording the desired product which was pur-
ified by crystallization from hexane/EtOAc. The
oxazinoquinoline 1 was obtained as a white solid (90
mg, 45% yield): Mp: 140–142 ꢁC (hexane, ethyl acetate).
IR (KBr) (cmꢀ1): 1070 (C-O-C, st.);1230 (ArC- O-C,
These compounds were tested in vitro by the National
Cancer Institute, and were evaluated against 60 human
tumor cell lines derived from eight cancer types (leuke-
mia, non-small cell lung cancer, small cell lung cancer,
colon cancer, CNS cancer, melanoma, ovarian cancer
and renal cancer).17,18 Representative results are sum-
marized in Table 1. Results are presented as log GI50,
where GI50 represents the molar concentration required
to inhibit cell growth by 50%.
1
st.). H NMR (CDCl3, 300 MHz) d(ppm): 3.16 (s, 3H,
CH3N);4.29 (cs, 4H, O CH2CH2O);4.87 (s, 2H, H-2);
4.90 (d, J=1.2 Hz, 2H, H-4);6.95 (s, 1H, H-6);7.18 (s,
1H, H-11);7.26 (s, 1H, H-5). 13C NMR (CDCl3,
75.5 MHz) d (ppm): 32.4 (CH3, CH3N);64.2 and 64.5
(CH2, OCH2CH2O);68.6 (CH , C4);81.3 (CH , C2);
2
2
In general, most of the compounds have only moderate
activity (all compounds showed 50% growth inhibition
at 10ꢀ4 M) (Table 1). With a few exceptions, all com-
pounds have similar activity across the cell lines;there is
little effect of linear and angular systems, or in the nat-
ure of the 4th ring. Moreover, compound 1, the most
active, showed selectivity to breast cancer (HS578T)
(GI50=1.10ꢀ8 M), and leukemia. Compound 2 has
selectivity against non-small cell lung cancer
(GI50=10ꢀ6), and breast cancer lines.
111.7 (CH, C11);111.9 (CH, C6), 116.4 (C, C5a);118.5
(C, C4a);129.1 (CH, C5);140.7 (C, C6a);143.4 (C,
C11a);146.2 (C, C10a);152.1 (C, C12a). MS (EI) ( m/z)
57 (26%);201 (40%);228 (45%, C 13H12N2O+2 );244
(1%, C13H12N2O+3 );258 (100%, C 14H14N2O+3 ). Anal.
calcd for (C14H14N2O3): C, 65.11%;H%, 5.46%;N,
10.85%. Found: C, 64.89%;H%, 5.67%;N, 10.75%.
4.1.2. 8 - Methyl - 2,3,8,9 - tetrahydro[1,4]dioxino[2,3-f]-
[1,3]oxazino[4,5-b]quinoline (5). The compound 5 was
prepared following the same procedure described above
for 1, starting from the aminoalcohol 16 (70 mg, 0.286
mmol). This methodology afforded 5 (42 mg, 0.162
mmol) as a white solid in 57% yield. Mp: 138–140 ꢁC
(hexane, ethyl acetate). IR (KBr) (cmꢀ1): 1066 (C-O-C,
In conclusion, our results demonstrate that the tetra-
cyclic compounds incorporating a 1,4-benzodioxine
group show reduced antitumor activity compared to
camptothecin. Studies aimed at increasing the anti-
tumor activity of other tetracyclic systems are currently
in progress.
1
st.);1242 (ArC- O-C, st.). H NMR (CDCl3, 300 MHz)
d(ppm): 3.17 (s, 3H, CH3N);4.33 (cs, 4H, O CH2CH2O);
4.89 (s, 2H, H-9);4.96 (s, 2H, H-11);7.09 (d, J=9.2 Hz,
1H, H-5);7.24 (d, J=9.2 Hz, 1H, H-6);7.71 (s, 1H, H-
12). 13C NMR (CDCl3, 75.5 MHz) d (ppm): 32.4 (CH3,
CH3N);64.2 and 64.6 (CH , OCH2CH2O);68.7 (CH ,
4. Experimental
4.1. General
2
2
C4);81.3 (CH , C2);114.6 (C, C12a);117.4 (C, C11a),
2
118.9 (CH, C6);120.4 (C, C4a);123.7 (CH, C12);136.5
(C, C4a);136.6 (C, C12b);142.8 (C, C6a);151.8 (C,
C7a). Anal. calcd for (C14H14N2O3): C, 65.11%;H%,
5.46%;N, 10.85%. Found: C, 64.96%;H%, 5.81%;N,
10.61%.
1H NMR spectra were recorded on a Varian Gemini-
300 or 500-spectrometer using tetramethylsilane as
internal standard and CDCl3 as solvent, chemical shifts
are given in ppm and coupling constants are expressed
in Hz. 13C NMR spectra were recorded on a Varian
Gemini 75.5 or 50.3 MHz spectrometer. Melting points
were determined with a Gallenkamp apparatus and are
uncorrected. IR spectra were recorded on a FTIR Per-
kin Elmer 1600 spectrophotometer. Mass spectra were
recorded on a Hewlett-Packard spectrometer 5988-A
(70 eV). Chromatography was carried out on SiO2
(silica gel 60, SDS, 60–200 mm). Microanalyses were
determined on a Carlo Erba 1106 Analyser at Serveis
Cientifico-Tecnics, Universitat de Barcelona and all the
new compounds have given C, H, N analyses with-
inꢂ0.4% of the theoretical values. All reagents were of
commercial quality or purified before use and the
organic solvents were of analytical grade or purified by
standard procedures.
4.1.3. 1-Methyl-2-oxo-1,2,8,9-tetrahydro[1,4]dioxino[2,3-
g][1,3]oxazino[4,5-b] quinoline (2). A suspension of the
aminoalcohol 15 (63 mg, 0.255 mmol) and sodium
methoxide (35 mg, 0.64 mmol) in 5 mL of dimethyl
carbonate was heated at 100 ꢁC for 24 h. Then, the sol-
vent was removed under reduced pressure. The solid
obtained was dissolved in CH2Cl2 and washed several
times with water. The washed organic layer was dried,
filtered and concentrated affording a crude mixture
which was purified by silica gel column chromato-
graphy. When a mixture of hexane/EtOAc, 70/30 was
used as eluent, a white solid was obtained (17 mg, 24%
yield) which was identified as the oxazinoquinoline 2:
Mp: 232–233 ꢁC (hexane, ethyl acetate). IR (KBr)
(cmꢀ1): 1064 (C-O-C);1244 (ArC- O-C);1730 (CO, st.).
1H NMR (CDCl3, 500 MHz) d (ppm): 3.51 (s, 3H,
CH3N);4.29 (cs, 4H, O CH2CH2O);5.19 (d, J=1.0 Hz,
2H, CH2OCO);7.07 (s, 1H, H-6);7.31 (s, 1H, H-11);
7.58 (d, J=0.5 Hz, 1H, H-5). 13C NMR (CDCl3,
75.5 MHz) d (ppm): 30.2 (CH3, CH3N);64.3 and 64.4
4.1.1. 1 - Methyl - 1,2,8,9 - tetrahydro[1,4]dioxino[2,3-g]-
[1,3]oxazino[4,5-b]quinoline (1). A suspension of the
aminoalcohol 15 (190 mg, 0.77 mmol), a catalytic
amount of PTSA, enough amount of molecular sieves 4
A and paraformaldehyde (212 mg, 2.35 mmol) in anhy-
drous toluene (25 mL) was stirred at 110 ꢁC for 24 h.
Then, the cooled mixture was filtered and the filtrate
was washed with a saturated solution of NaHCO3. The
(CH2, OCH2CH2O);66.1 (CH , CH2OCO);112.0 (CH,
2
C6);113.4 (CH, C11);113.8 (C, C4a);120.6 (C, C5a);
130.4 (CH, C5);142.9 (C, C11a);143.3 (C, C6a);147.3

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953
(C, C10a);147.8 (C, C12a);153.3 (C;C2). MS (EI) ( m/z)
63 (60%), 83 (100%), 85 (65%), 201 (38%), 227 (33%,
C13H12N2O+2 ), 272 (34%, C14H12N2O4). Anal. calcd for
(C14H12N2O4): C, 61.76%;H, 4.44%;N, 10.29%.
Found: C, 61.55%;H, 4.68%;N, 10.09%.
4.2.2. 4.4.2. 8,10 - Dimethyl - 9 - oxo - 2,3,8,9,10,11-hexa-
hydro-[1,4]dioxino[2,3-f]pyrimido[4,5-b] quinoline (7).
Starting from the amine (76 mg, 0.293 mmol), and fol-
lowing the general procedure described before the title
compound was obtained as a white solid (37 mg, 0.129
mmol) in a 44% yield. Mp: 232–234 ꢁC (hexane, ethyl
acetate). IR (KBr) (cmꢀ1): 1064 (C-O-C, st);1250 (ArC-
O-C, st);1670 (CO, st). 1H NMR (CDCl3, 300 MHz) d
4.1.4. 8-Methyl-9-oxo-2,3,8,9-tetrahydro[1,4]dioxino[2,3-
f][1,3]oxazino[4,5-b] quinoline (6). Following the same
procedure described above, and starting from the
aminoalcohol 16 (85 mg, 0.348 mmol) the compound 6
(45 mg, 0.4 mmol) was obtained as a white solid in 48%
yield. Mp: 214–215 ꢁC (hexane, ethyl acetate). IR (KBr)
(cmꢀ1): 1095 (C-O-C);1288 (ArC- O-C);1698 (CO, st.).
1H NMR (CDCl3, 300 MHz) d (ppm): 3.59 (s, 3H,
CH3N);4.40 (cs, 4H, O CH2CH2O);5.32 (d, J=1.1 Hz,
2H, CH2OCO);7.27 (d, J=9 Hz, 1H, H-5);7.46 (dd,
J=9.0, J=0.8 Hz, 1H, H-6);8.09 (d, J=0.8 Hz, 1H, H-
12). 13C NMR (CDCl3, 75.5 MHz) d (ppm): 30.0 (CH3,
CH3N);64.5 and 64.6 (CH , OCH2CH2O);66.2 (CH ,
(ppm): 3.07 (s, 3H, CH3-N);3.53 (s, 3H, CH N);4.37
3
(cs, 4H, CH2-);4.46 (d, J=1.3 Hz, 2H, C11-H2);7.20
(d, J=9.1 Hz, 1H, H-5);7.39 (dd, J=9.1 Hz, J=0.8 Hz,
1H, H-6);7.96 (d, J=0.8 Hz, 1H, H-12). 13C NMR
(CDCl3, 75.5 MHz) d (ppm): 28.9 (CH3);35.5 (CH );
3
49.1 (CH2, C-4);64.3, and 64.6 (CH 2, OCH2CH2O),
115.1 (C, C-11a);116.6 (C, C-12a);120.5 (CH, C6);121.3
(CH, C5);125.6 (CH, C12);136.2 (C, C12b);138.1 (C,
C4a);142.2 (C, C6a);148.9 (C, C7a);155.1 (C, C9).
Anal. calcd for (C15H15N3O3): C, 63.15%;H, 5.30%;N,
14.73%. Found: C, 62.82%;H, 5.64%;N, 14.51%.
2
2
CH2OCO);114.8 (C, C11a);117.0 (C, C12a);120.8 (C,
C6);122.0 (CH, C5);125.2 (CH, C12);136.5 (C, C12b);
138.8 (C, C4a);142.3 (C, C6a);147.5 (C, C7a);152.3 (C;
C9). Anal. calcd for (C14H12N2O4): C, 61.76%;H,
4.44%;N, 10.29%. Found: C, 61.60%;H, 4.68%;N,
9.98%.
4.3. General procedure for obtaining pyrimidoquinolines
(4 and 8)
To a solution of the corresponding amine (1 mmol) in
dry toluene (50 mL), a catalytic amount of the PTSA,
molecular sieves 4 A (200 mg), and paraformaldehyde (3
mmol) were added. The mixture was stirred at 110 ꢁC
for 24 h. After cooling, the mixture was made basic with
saturated solution of NaHCO3, and extracted with ether
(2ꢃ30 mL). The organic layers were dried, the solvent
was removed under vacuo to give the desired pyr-
imidoquinoline. The crude product was recrystallized
from hexane/ethyl acetate mixtures.
4.2. General procedure for the preparation of 2-oxopyr-
imidoquinolines (3 and 7)
A solution of the corresponding amine (1 mmol) in dry
THF (6 mL) was cooled to 0 ꢁC under argon atmos-
phere. Then a solution of butyllithium (1.2 mmol) in
hexane (1.6 M) was dropwise added. The mixture was
stirred at the same temperature for 30 min, and then at
room temperature for another 2 h. After a solution of
dimethyl carbonate (1.2 mmol) was added, the resulting
mixture was stirred at room temperature for 12 h. A
solution of saturated NH4Cl was added, and the reac-
tion mixture was extracted with ether (3ꢃ20 mL), dried
over Na2SO4, filtered off, and the solvent was removed
under reduced pressure. The crude product was purified
by column chromatography eluting with hexane/ethyl
acetate or by crystallisation.
4.3.1. 1,3 - Dimethyl - 1,2,3,4,8,9 - hexahydro - [1,4]di-
oxino[2,3-g]pyrimido[4,5-b]quinoline (4). Starting from
the amine (111 mg, 0.428 mmol), and following the
general procedure described before, the title compound
was obtained as a white solid (85.9 mg, 0.316 mmol) in a
74% yield. Mp: 139–141 ꢁC (hexane, ethyl acetate). IR
(KBr) (cmꢀ1): 1060 (C-O-C, st);1242 (ArC- O-C, st). 1H
NMR (CDCl3, 300 MHz) d (ppm): 2.48 (s, 3H, CH3-N);
3.20 (s, 3H, CH3N);3.90 (cs, 2H, CH –);4.19 (s, 2H,
2
C4-H2);4.29 (cs, 4H, CH );6.94 (s, 1H, H-6);7.25 (s,
2
4.2.1. 1,3-Dimethyl-2-oxo-1,2,3,4,8,9-hexahydro-[1,4]di-
oxino[2,3-g]pyrimido[4,5-b] quinoline (3). Starting from
the amine (97 mg, 0.374 mmol) in THF (6 mL), and
following the general procedure described above the
title compound was obtained as a white solid (70 mg,
0.245 mmol) in a 66% yield. Mp: 220–222 ꢁC (hexane,
ethyl acetate). IR (KBr) (cmꢀ1): 1062 (C-O-C, st);1247
1H, H-11);7.30 (s, 1H, H-5). 13C NMR (CDCl3,
75.5 MHz) d (ppm): 34.1 (CH3);41.0 (CH );55.5 (CH ,
3
2
C-4);64.3 and 64.5 (CH 2, OCH2CH2O), 72.2 (CH2);
111.2 (CH, C-11);111.7 (CH, C-6);115.7 (C, C5a);
118.5 (C, C4a);131.7 (CH, C5);140.4 (C, C10a);146.1
(C, C6a);146.1 (C, C10a);152.2 (C-12a). Anal. calcd for
(C15H17N3O2.2H2O): C, 58.62%;H, 6.89%;N, 13.67%.
Found: C, 58.87%;H, 6.57%;N, 13.74%.
(ArC-O-C, st);1662 (CO, st).
1H NMR (CDCl3,
500 MHz) d (ppm): 3.07 (s, 3H, CH3-N);3.53 (s, 3H,
CH3N);4.35 (cs, 4H, CH –);4.43 (d, J=1 Hz, 2H, C4-
4.3.2. 8,10 - Dimethyl - 2,3,8,9,10,11 - hexahydro-
[1,4]dioxino[2,3-f]pyrimido[4,5-b] quinoline (8). Starting
from the amine (79 mg, 0.304 mmol), and following the
general procedure described before, the title compound
was obtained as an oil (72 mg, 0.265 mmol) in a 87%
2
H2);7.07 (s, 1H, H-6);7.33 (s, 1H, H-11);7.55 (s, 1H,
H-5). 13C NMR (CDCl3, 75.5 MHz) d (ppm): 29.0
(CH3);35.5 (CH 3);48.9 (CH 2, C-4);64.3 and 64.4 (CH 2,
OCH2CH2O), 111.6 (CH, C-6);113.0 (CH, C-11);114.1
(C, C4a);120.3 (C, C5a);130.9 (CH, C5);142.6 (C,
C11a);142.8 (C, C6a);146.8 (C, C10a);149.2 (C, C12a);
155.2 (C-2). Anal. calcd for (C15H15N3O3): C, 63.15%;
H, 5.30%;N, 14.73%. Found: C, 62.79%;H, 5.57%;N,
14.58%.
1
yield. This compound was unstable, and only the H
NMR was realized.
1H NMR (CDCl3, 300 MHz) d (ppm): 2.39 (s, 3H, CH3-
N);3.10 (s, 3H, CH N);3.86 (s, 2H, CH –);4.24 (cs,
3
2

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954
4H, CH2);6.98 (d, J=9.1 Hz,1H, H-5);7.13 (d, J=9.1
Hz, 1H, H-6);7.64 (s, 1H, H-12).
CHO). 13C NMR (CDCl3, 75.5 MHz) d (ppm): 64.3 and
64.6 (CH2, OCH2CH2O);119.0 (C, C10a);121.0 (CH,
C6);125.2 (C, C9);125.9 (CH, C5);133.8 (CH, C10);
137.8 (C, C10b);140.3 (C, C4a);144.8 (C, C6a);148.0
(C, C8);189.0 (C, CHO). MS (EI) ( m/z) 83 (100%), 192
(59%, C9H3ClNO+2 );193 (58%, C 9H4ClNO+2 );220
(1%, C11H7ClNO+2 );249 (59%, C 12H8ClO+3 ). Anal.
calcd for (C12H8ClNO3) C, 57.73%;H, 3.23%;N,
5.61%. Found: C, 57.45%;H, 3.51%;N, 5.74%.
4.3.3. N-(2,3-Dihydro-1,4-benzodioxin-6-yl)acetamide (10).
A solution of 9 (2.61 g, 17.26 mmol) in 50 mL of acetic
anhydride was stirred at 140 ꢁC for 8 h. The reaction
mixture was cooled at 0 ꢁC, basified with cold 5 N
NaOH and extracted with CH2Cl2 (3ꢃ30 mL). Removal
of the solvent, and purification by silica gel column
chromatography with 4:6 EtOAc/hexane gave 2.9 g
(15.01 mmol) of 10 (87%) as a white solid. Mp: 129–
130 ꢁC (hexane, ethyl acetate). IR (KBr), (cmꢀ1): 1067
(C-O-C, st);1258 (ArC- O-C, st);1664 (C ¼O, st);3312
4.3.7. 7-Methylamino-2,3-dihydro[1,4]dioxino[2,3-g]quin-
oline-8-carbaldehyde (13). To a solution of the aldehyde
11 (179 mg, 0.712 mmol) in methanol, a solution of 50
mL of methylamine (40% in water) solution was added
and the resulting mixture was stirred at 90 ꢁC for 24 h.
Then, the methanol was removed and the suspension
obtained was acidified with HCl 1N. The resulting mix-
ture was stirred at room temperature for 12 h, then it
was basified with a solution of NaOH 5N and extracted
with CH2Cl2 (3ꢃ20 mL). The combined organic layers
were dried, filtered and the solvent removed. The crude
product obtained was purified by silica gel column
chromatography yielding 13 (151 mg, 87% yield) as an
orange solid. Mp: 150–152 ꢁC (hexane, ethyl acetate).
IR (KBr) (cmꢀ1): 1063 (C-O-C, st.);1247 (ArC- O-C,
st.);1664 (CO, st.). 1H NMR (CDCl3, 300 MHz) d
(ppm): 3.05 (d, J=4.9 Hz, 3H, CH3-NH);4.26 (cs, 4H,
OCH2CH2O);6.98 (s, 1H, H-10);7.05 (s, 1H, H-5);7.81
(bs, 1H, NH);7.91 (s, 1H, H-9);9.77 (s, 1H, CHO). 13C
NMR (CDCl3, 75.5 MHz) d (ppm): 27.5 (CH3, CH3NH);
64.0 and 64.7 (CH2, OCH2CH2O);111.4 (CH, C5);113.6
(CH, C10);116.1 (C, C8);117.1 (C, C9a);141.0 (C, C10a);
146.8 (CH, C9);147.8 (C, C5a);150.4 (C, C4a);154.8
(C, C7);192.6 (CH, CHO). MS (EI) ( m/z) 70 (99%);188
(100%);215 (26%, C 12H11N2O+2 );244 (97%, C 13H12N2O3).
Anal. calcd for (C13H12N2O3): C, 63.93%;H, 4.95%;N,
11.47%. Found: C, 63.63%;H, 5.31%;N, 11.76%.
1
(NH, st). H RMN (CDCl3, 300 MHz) (ppm): 2.14 (s,
3H, CH3-CO);4.25 (m, 4H, O CH2CH2O);6.79 (d,
J=8.5 Hz, 1H, H-8);6.86 (dd, J1=8.5 Hz, J2=2.3 Hz,
1H, H-7);7.08 (bs, 1H, NH);7.12 (d, J=2.3 Hz, 1H, H-
5). 13C-RMN (CDCl3-CD3OD, 50.3 MHz) (ppm): 22.9
(CH3, CH3-CO);63.8 and 63.9 (CH 2, OCH2CH2O);
109.4 (CH, C5);113.3 (CH, C7);116.5 (CH, C8);131.5
(C, C6);139.8 (C, C8a);142.8 (C, C4a);169.5 (C, CO).
Anal. calcd for (C14H12N2O4): C, 62.17%, H%, 5.74%,
N, 7.25%. Found: C, 61.98%;H, 5.91%;N, 7.12%.
4.3.4. 7-Chloro-2,3-dihydro[1,4]dioxino[2,3-g]quinoline-8-
carbaldehyde (11) and 8-Chloro-2,3-dihydro[1,4]di-
oxino[2,3-f]quinoline-9-carbaldehyde (12). A solution of
phosphorus oxychloride (4 mL, 43.5 mmol) and anhy-
drous DMF (1.4 mL, 18.02 mmol) was stirred under
argon atmosphere at 0 ꢁC for 10 min. Then, the acet-
amide 10 (1.13 g, 5.84 mmol) was slowly added and the
reaction mixture was stirred at 90 ꢁC for 12 h. After, the
cooled mixture was poured into ice (20 mL). The sus-
pension obtained was filtered and the solid was dried in
vacuo (P2O5) to give a yellow solid that was purified by
silica gel column chromatography. Compound 12 was
obtained as a yellow solid (66 mg, 5% yield) when a mix-
ture of hexane/EtOAc, 80/20 was used as eluent. Com-
pound 11, white solid (1.04 g, 71% yield) was obtained
using a mixture of hexane/EtOAc in the ratio 70/30.
4.3.8. 8-Methylamino-2,3-dihydro[1,4]dioxino[2,3-f]quin-
oline-9-carbaldehyde (14). Following the same proce-
dure described above for 13, and starting from the
aldehyde 12 (0.73 mmol) the desired aminoaldehyde 14
(172 mg, 0.704 mmol) was obtained as a yellow solid in
95% yield. Mp: 158–159 ꢁC (hexane, ethyl acetate). IR
(KBr) (cmꢀ1): 1057 (C-O-C, st.);1179 (ArC- O-C, st.);
4.3.5. Compound (11). Mp: 227–229 ꢁC (hexane, ethyl
acetate). IR (KBr) (cmꢀ1): 1061 (C-O-C, st.);1250
(ArC-O-C, st.);1685 (CO, st.). 1H NMR (CDCl3,
500 MHz) d (ppm): 4.41 (cs, 4H, OCH2CH2O);7.34 (s,
1H, H-5);7.48 (d, J=0.5 Hz, 1H, H-10);8.54 (d, J=0.5
Hz, 1H, H-9), 10.48 (s, 1H, CHO). 13C NMR (CDCl3,
75.5 MHz) d (ppm): 64.1 and 64.6 (CH2, OCH2CH2O);
113.6 (CH, C5);113.8 (CH, C10);122.5 (C, C9a);124.7
(C, C8);138.5 (CH, C9);145.4 (C, C10a);146.4 (C, C5a);
148.7 (C, C7);150.5 (C, C4a);189.2 (CH, CHO). MS
(EI) (m/z) 83 (100%);192 (60%, C 9H3ClNO+2 );193
(56%, C9H4ClNO+2 );220 (20%, C 11H7ClNO+2 );249
(80%, C12H7ClNO2+). Anal. calcd for (C12H8ClNO3):
C, 57.73%;H, 3.23%;N, 5.61%. Found: C, 57.51%;H,
3.42%;N, 5.72%.
1
1665 (CO, st.). H NMR (CDCl3, 300 MHz) d (ppm):
3.01 (d, J=4.9 Hz, 3H, CH3-NH);4.24 (cs, 4H, O CH2-
CH2O);7.07 (d, J=9.1 Hz, 1H, H-5);7.13 (d, J=9.1
Hz, 1H, H-6);7.73 (bs, 1H, NH);8.26 (s, 1H, H-10);
9.78 (s, 1H, CHO). 13C NMR (CDCl3, 75.5 MHz)
d(ppm): 27.3 (CH3, CH3NH);64.0 and 64.7 (CH
OCH2CH2O);113.6 (CH, C9);116.3 (C, C10a);118.8
(CH, C6);125.3 (CH, C5);136.0 (C, C10b);137.4 (C,
C4a);141.4 (CH, C10);146.4 (C, C6a);154.2 (C, C8);
,
2
192.6 (CH, CHO). MS (EI) (m/z) 70 (99%);188 (100%);
215 (26%, C12H11N2O+2 );244 (97%, C 13H12N2O3).
Anal. calcd for (C13H12N2O3): C, 63.93%;H, 4.95%;N,
11.47%. Found: C, 63.50%;H, 5.05%;N, 11.34%.
4.3.6. Compound (12). Mp: 187–189 ꢁC (hexane, ethyl
acetate). IR (KBr) (cmꢀ1): 1083 (C-O-C, st.);1256
(ArC-O-C, st.);1681 (CO, st.). 1H NMR (CDCl3,
500 MHz) d (ppm): 4.36 (cs, 4H, CH2O);7.38 (d,
J1=9.2, J2=0.5 Hz, 1H, H-5);7.49 (dd, J1=9.2 Hz,
J2=0.5 Hz, 1H, H-6), 8.88 (s, 1H, H-10);10.45 (s, 1H,
4.4. Preparation of alcohols (15–18). General procedure
A solution of the corresponding aldehyde (1 mmol) in
methanol (10 mL) was cooled at 0 ꢁC and NaBH4 (4.5

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M. T. Vazquez et al. / Bioorg. Med. Chem. 12 (2004) 949–956
955
mmol) was added. The solution obtained was stirred at
0 ꢁC for 10 min and then it was stirred at room tem-
perature for 25 min more. After, the solvent was
removed under reduced pressure and 20 mL of water
were added. The suspension obtained was extracted
several times with CH2Cl2 and the combined organic
layers were dried, filtered and concentrated to yielding
the desired aminoalcohol. The obtained alcohol was
used without further purification or by silica gel column
chromatography.
4.4.3. 7-Chloro - 8 - hydroxymethyl - 2,3 - dihydro[1,4]di-
oxino[2,3-g]quinoline (17). Compound 17 was obtained
as a white solid (362 mg, 90% yield) starting from a
mixture of the aldehyde 11 (400 mg, 1.6 mmol) and
NaBH4 (60 mg, 1.6 mmol) in methanol (20 mL) and
following the general procedure. Mp: 207–209 ꢁC
(hexane, ethyl acetate). IR (KBr) (cmꢀ1): 1075, (C-O-
C, st);1235 (ArC- O-C, st);3280 (–OH, st). 1H NMR
(CDCl3, 500 MHz) d (ppm): 4.36 (cs, 4H, CH2O);4.60
(dd, J1=5.7 Hz, J2=1.0 Hz, 2H, CH2OH);5.56 (t,
J=5.7 Hz, 1H, OH);7.31 (s, 1H, H-5);7.47 (s, 1H, H-
10);8.22 (s, 1H, H-9). 13C NMR (CDCl3, 75.5 MHz)
4.4.1. 7-Methylamino-8-hydroxymethyl-2,3-dihydro[1,4]-
dioxino[2,3-g]quinoline (15). Method A. Compound 15
was obtained as a yellow solid (173 mg, 98% yield)
starting from a solution of the aminoaldehyde 13 (174
mg, 0.712 mmol) and NaBH4 (124 mg, 3.27 mmol) in
methanol (20 mL) and following the general procedure,
described above.
d (ppm): 64.0 (CH2, CH2OH);64.3 and 64.5 (CH
OCH2CH2O), 112.0 (CH, C10);112.3 (CH, C5);
123.3 (C, C9a);131.7 (C, C8);134.7 (CH, C9);142.6
(C, C5a);144.8 (C, C10a);146.8 (C, C7a);147.4 (C,
,
2
C4a). Anal. calcd for (C12H10ClNO3): C, 57.27%;H,
4.01%;N, 5.57%. Found: C, 57.58%;H, 3.85%;N,
5.51%.
Method B. A suspension of the alcohol 17 (400 mg, 1.6
mmol) and a catalytic amount of KI in 35 mL of
methylamine (40% in water) was stirred at 90 ꢁC for 14
days, adding 5 mL of methylamine and a catalytic
amount of KI every 12 h. Then, the cooled mixture
was extracted with CH2Cl2 (3ꢃ40 mL) and the
combined organic layers were dried, filtered and
concentrated under reduced pressure yielding 15 as a
yellow solid (354 mg, 90% yield). This compound was
used without further purification. Mp: 189–190 ꢁC
(hexane, ethyl acetate). IR (KBr) (cmꢀ1): 1070 (C-O-C,
st.);1239 (ArC- O-C, st.);3376 (–OH, st.). 1H NMR
(CDCl3, 500 MHz) d (ppm): 3.07 (d, J=3.5 Hz, 3H,
CH3NH);4.30 (cs, 4H, CH O);4.56 (s, 2H, CH OH);
5.66 (bs, 1H, OH);6.90 (s, 1H, H-10);7.19 (s, 1H, H-5);
7.20 (s, 1H, H-9). 13C NMR (CDCl3, 75.5 MHz) d
(ppm): 28.1 (CH3, CH3NH);64.0 (CH , CH2OH);64.3
2
and 64.6 (CH2, OCH2CH2O);111.2 (CH, C5);112.3
(CH, C10);118.1 (C, C9a);120.3 (C, C8);133.9 (CH,
C9);140.4 (C, C10a);143.7 (C, C5a);146.5 (C, C4a);
156.1 (C, C7). Anal. calcd for (C13H14N2O3): C,
63.40%;H, 5.73%;N, 11.38%. Found: C, 63.11%;H,
5.71%;N, 11.25%.
4.4.4. 8 - Chloro - 9 - hydroxymethyl - 2,3 - dihydro[1,4]-
dioxino[2,3-f]quinoline (18). Following the general pro-
cedure for the preparation of alcohol described before,
the compound 18 was obtained as a white solid (16 mg,
80% yield) starting from a mixture of the aldehyde 12
(205 mg, 0.82 mmol) and NaBH4 (33 mg, 0.89 mmol) in
methanol (12 mL) and following the general procedure.
Mp: 173–174 ꢁC (hexane, ethyl acetate). IR (KBr)
(cmꢀ1): 1071, (C-O-C, st);1243 (ArC- O-C, st);3273 (–
OH, st). 1H NMR (CDCl3, 500 MHz) d (ppm): 4.42 (cs,
4H, CH2O);4.65 (dd, J1=5.5 Hz, J2=1.0 Hz, 2H,
CH2OH);5.66 (t, J=5.5 Hz, 1H, OH);7.37 (d, J=9.0
Hz, 1H, H-5);7.45 (dd, J=9.0 Hz, J=0.5 Hz, 1H, H-6);
8.44 (d, J=0.5 Hz, 1H, H-10). 13C NMR (CDCl3,
75.5 MHz) d (ppm): 60.1 (CH2, CH2OH);64.4 and 64.7
(CH2, OCH2CH2O), 119.4 (CH, C10a);120.5 (CH, C6);
122.4 (CH, C5);128.5 (CH, C10);133.4 (C, C9);136.1
(C, C10b);139.9 (C, C4a);141.8 (C, C6a);146.4 (C, C8).
Anal. calcd for (C12H10ClNO3): C, 57.27%;H, 4.01%;
N, 5.57%. Found: C, 57.12%;H, 4.34%;N, 5.89%.
2
2
Acknowledgements
4.4.2. 8-Methylamino-9-hydroxymethyl-2,3-dihydro[1,4]-
dioxino[2,3-f]quinoline (16). Following the general pro-
cedure of reduction of aldehydes described before,
and starting from the aminoaldehyde 14 (150 mg,
0.614 mmol) the aminoalcohol 16 was obtained
(147 mg, 0.596 mmol) as a yellow solid in 97% yield.
Mp: 183–184 ꢁC (methanol). IR (KBr) (cmꢀ1): 1088
(C-O-C, st.);1242 (ArC- O-C, st.);3380 (–OH, st.). 1H
NMR (CDCl3, 500 MHz) d (ppm): 3.04 (s, 3H,
The authors express their gratitude to the Generalitat de
Catalunya, Spain (01-SGR-00085) and to the Ministerio
de Ciencia y Tecnologıa (MCYT, BQU 2002-00148) for
the financial support.
References and notes
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M. T. Vazquez et al. / Bioorg. Med. Chem. 12 (2004) 949–956
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