Novel approach towards the synthesis of 3,3a,4,5-tetrahydroquinolino[4,3-c] isoxazole derivatives: Application to the preparation of previously unattainable 3a,4-dihydroazabenzopyrano[4,3-c]isoxazole scaffolds

Article abstract of DOI:10.1055/s-2005-921909

A novel synthetic approach towards the preparation of 3-substituted-7,8- dimethoxy-3,3a,4,5-tetrahydroquinolino[4,3-c]isoxazole derivatives is reported. Further application of this methodology to the preparation of previously unattainable 3a,4-dihydroazab

Full text of DOI:10.1055/s-2005-921909

LETTER
3139
Novel Approach towards the Synthesis of 3,3a,4,5-Tetrahydroquinolino-
[4,3-c]isoxazole Derivatives: Application to the Preparation of Previously
Unattainable 3a,4-Dihydroazabenzopyrano[4,3-c]isoxazole Scaffolds
N
ovel App
e
roach towa
s
r
ds 3,3a,4
ú
, 5-Tetrahydr
s
oquinolino[4,3-
A
c]isoxazoles lcázar,* José Manuel Alonso, José Ignacio Andrés, José Manuel Bartolomé, Javier Fernández
Johnson & Johnson Pharmaceutical Research and Development Division, Janssen-Cilag S.A., Jarama 75, 45007 Toledo, Spain
Fax +34(925)245771; E-mail: jalcazar@prdes.jnj.com
Received 27 September 2005
derivatives, the desired compounds were only obtained in
very low yields (<5%), making further exploration around
this core difficult.3 Furthermore, the application of this ap-
proach to the synthesis of some analogues of prototype 1
presenting a pyridine moiety replacing the phenyl ring
proved to be unsuccessful.
Abstract: A novel synthetic approach towards the preparation of
3-substituted-7,8-dimethoxy-3,3a,4,5-tetrahydroquinolino[4,3-
c]isoxazole derivatives is reported. Further application of this meth-
odology to the preparation of previously unattainable 3a,4-dihy-
droazabenzopyrano[4,3-c]isoxazole derivatives is also described.
Key words: isoxazolines, fused-ring systems, ring closure, hetero-
cycles, antidepressants
In order to circumvent those issues, novel approaches to-
wards the preparation of these analogues were envisaged.
After prospecting several alternatives, the construction of
the tricyclic core by intramolecular cyclization of the
appropriate isoxazoline intermediates (Scheme 1, path B)
emerged as the best option. Herein we report an improved
method for the synthesis of 7,8-dimethoxy-3,3a,4,5-tet-
rahydroquinolino[4,3-c]isoxazole derivatives and also the
application of this novel strategy to the synthesis of 3a,4-
dihydroazabenzopyrano[4,3-c]isoxazole derivatives pre-
viously unattainable via the former procedure.
The potential antidepressant activity of 3-piperazinyl-
methyl-3a,4-dihydro-3H-[1]benzopyrano[4,3-c]isoxazole
derivatives represented by compound 1 (Figure 1) was re-
cently described by our group.1–3 This class of compounds
presents an interesting combination of activities acting as
dual a2-adrenoceptor antagonists and 5-HT reuptake
inhibitors. Several research programs around these
structures have been initiated at Johnson & Johnson
Pharmaceutical Research and Development to fully
explore the SAR of this family of compounds. From this
exploration, 3-substituted-7,8-dimethoxy-3,3a,4,5-tetra-
hydroquinolino[4,3-c]isoxazole derivatives emerged as
potential additional promising leads for further pharma-
cological evaluation (Figure 1, compound 2).3
Path A
R2
OH
O
N
X
N
R2
R3
R1
R3
X
R1
O
R2
R3
X = O, NH
N
X
O
N
N
O
O
H
1: X = O
2: X = NH
Path B
R2
X
O
O
N
N
R2
R3
R1
R1
LG
Figure 1 Lead tricyclic isoxazoline derivatives with potential anti-
depressant activity.
R3
X
XH
The preparation of these analogues was firstly achieved
following the original procedure described by Baraldi et
al. (Scheme 1).4 This procedure involves the generation of
the tricyclic system by intramolecular 1,3-dipolar cy-
cloaddition, via nitrile oxides, of the appropriate inter-
mediates (Scheme 1, path A). Unfortunately, when this
approach was applied to the preparation of 7,8-
dimethoxy-3,3a,4,5-tetrahydroquinolino[4,3-c]isoxazole
LG = Leaving group
Scheme 1 Retrosynthetic analyses towards the synthesis of tricyclic
isoxazoline cores.
Thus, commercially available 6-nitroveratraldehyde 3
was chosen as starting material for the application of this
new procedure (Scheme 2). Conversion of 3 into the cor-
responding oxime, using standard procedures, followed
by oxidation to the corresponding nitrile oxide and in situ
1,3-dipolar cycloaddition with dimethyl fumarate afford-
ed the isoxazoline intermediate 4. The relative trans dis-
position of substituents at positions 3 and 4 of the
SYNLETT 2005, No. 20, pp 3139–3141
1
9
.1
2
.2
0
0
5
Advanced online publication: 04.11.2005
DOI: 10.1055/s-2005-921909; Art ID: G29505ST
© Georg Thieme Verlag Stuttgart · New York

3140
J. Alcázar et al.
LETTER
O
O
O
N
OMs
N
N
OMs
CO2Me
O
O
O
O
O
O
O
O
O
e, f
a, b
c, d
H
CO2Me
NO2
OMs
(89%)
(75%)
NO2
NO2
N
(83%)
H
3
4
5
6
Scheme 2 Reagents and conditions: (a) NH2OH·HCl, NaOAc, EtOH, r.t., 1 h; (b) dimethyl fumarate, NaClO, Et3N, CH2Cl2, r.t., 2 h;
(c) NaBH4, MeOH–THF, 0 °C, 2 h; (d) MeSO2Cl, Et3N, CH2Cl2, 0 °C, 30 min; (e) H2, Pd/C, THF–H2O, r.t., 24 h; (f) Et3N, THF, reflux, 24 h.
isoxazoline ring was predetermined by the trans stereo- For the synthesis of the 3-substituted 3a,4-dihydro-6-aza-
chemistry of the alkene fragment and was unequivocally 3H-[1]benzopyrano[4,3-c]isoxazole derivative 14, nu-
assigned by NMR analysis. Simultaneous reduction of cleophilic aromatic substitution reaction was chosen as fi-
both ester groups with sodium borohydride in a mixture of nal cyclization step. O-Alkylation or Mitsunobu reactions
tetrahydrofuran–methanol5 followed by reaction of the were tried unsuccessfully as 2-hydroxypyridines mainly
dihydroxy derivative obtained with methanesulfonyl exist in the pyridone form.10 Thus, 5-[2-bromopyridyl-3-
chloride furnished compound 5. Further reduction of the yl]isoxazoline derivative 13 was prepared from commer-
nitro group and subsequent cyclization by intramolecular cially available 2-bromopyridine-3-carboxaldehyde 12
N-alkylation reaction of the amino group with the following the same sequence of reactions already de-
adjacent methanesulfonyl group afforded compound 6.6 scribed (Scheme 4). In this case the oxidizing system
This intermediate additionally bears a second methane- NCS/pyridine was found to be optimal for the 1,3-dipolar
sulfonyl group ready for further derivatization. For in- cycloaddition reaction. Then, reduction of both esters of
stance, preparation of compound 2 could be easily 13 to the corresponding hydroxy groups followed by in-
performed by simple reaction of intermediate 6 with tramolecular nucleophilic aromatic substitution reaction
trans-1-(2-methyl-3-phenylpropenyl)piperazine with an promoted by basic media afforded desired scaffold 1411 in
overall yield of 26%, what clearly improved the result ob- low yield but easily isolated after purification by standard
tained with the previous procedure (2%).3 Moreover, the flash chromatography. In this case, again the stereo-
excellent overall yield obtained in the synthesis of scaf- chemistry of both stereocenters was not affected by the
fold 6 offered clear advantages for further exploration cyclization step.
around this heterocyclic system.
O
O
N
Application of this strategy to the synthesis of 3a,4-dihy-
dro-7-aza-3H-[1]benzopyrano[4,3-c]isoxazole derivative
11 is shown in Scheme 3. Thus, MEM-protected 3-hy-
droxypyridine 77 was first lithiated at position 4 and then
the anion was reacted with methyl formate furnishing 4-
carboxaldehyde pyridine derivative 8. Then, the sequence
of oxime formation, oxidation and 1,3-dipolar cycloaddi-
tion reactions yielded diester 9. The relative stereochem-
istry of both stereocenters was again predetermined by the
trans configuration of the alkene and remained unaltered
during the rest of the synthesis procedure. Subsequent re-
duction of both ester groups followed by MEM-deprotec-
tion in acidic media afforded trihydroxy derivative 10.
Finally, the 3a,4-dihydro-7-aza-3H-[1]benzopyrano[4,3-
c]isoxazole core 11 could be prepared via intramolecular
Mitsunobu reaction between the aromatic OH group and
the closest hydroxyalkyl moiety.8 This novel tricyclic
system9 presented a primary hydroxy group suitable for
further derivatization.
CO2Me
a, b
CO2Me
(50%)
N
Br
N
Br
12
13
c, d
(13%)
O
N
OH
H
N
O
14
Scheme 4 Reagents and conditions: (a) NH2OH·HCl, NaOAc,
EtOH, r.t., 16 h; (b) dimethyl fumarate, NCS, pyridine, Et3N, CHCl3,
reflux, 2 h; (c) NaBH4, THF–H2O, 0 °C, 1.5 h; (d) K2CO3, methyl iso-
butyl ketone, reflux, 16 h.
O
O
O
O
N
N
OH
N
OH
CO2Me
b, c
c, d, e
(34%)
f
a
H
CO2Me
OMEM
N
N
N
N
N
(80%)
(21%)
(98%)
OH
OMEM
OMEM
OH
O
7
8
9
10
11
Scheme 3 Reagents and conditions: (a) BuLi, TMEDA, methyl formate, Et2O, 0 °C to r.t., 16 h; (b) NH2OH·HCl, NaOAc, EtOH, r.t., 16 h;
(c) dimethyl fumarate, NaClO, Et3N, CH2Cl2, r.t., 16 h; (d) LiAlH4, THF, 0 °C, 2 h; (e) TFA, CH2Cl2, r.t., 16 h; (f) polymer-supported PPh3,
Et3N, DEAD, THF, reflux, 16 h.
Synlett 2005, No. 20, 3139–3141 © Thieme Stuttgart · New York

LETTER
Novel Approach towards 3,3a,4,5-Tetrahydroquinolino[4,3-c]isoxazoles
3141
dried (Na2SO4), filtered and evaporated. The residue was
purified by short open-column chromatography on silica gel
(CH2Cl2–EtOAc, 4:1 and EtOAc) yielding compound 6 as a
colorless syrup (4 mmol, 1.36 g, 75%).
In conclusion, the synthesis of 3-substituted 7,8-
dimethoxy-3,3a,4,5-tetrahydroquinolino[4,3-c]isoxazole
derivatives has been clearly improved applying a new
synthetic approach. This strategy has been successfully
applied to the preparation of previously unattainable 3-
substituted 3a,4-dihydroazabenzopyrano[4,3-c]isoxazole
analogues as well. Additionally, three different approach-
es for the final cyclization step, intramolecular N-alkyla-
tion, Mitsunobu and aromatic nucleophilic substitution
reactions, have been used, what clearly highlight the
versatility of this new procedure. Further applications of
these intermediates to the preparation of biologically
active compounds will be matter of future publications.
Representative analytical data for compound 6: foam. 1H
NMR (400 MHz, DMSO-d6, 25 °C): d = 6.90 (s, 1 H, H-9),
6.30 (s, 1 H, H-6), 6.12 (s, 1 H, NH), 4.62 (m, 1 H,
CH2OMs), 4.50 (m, 2 H, H-3 and CH2OMs), 3.72 (s, 3 H,
CH3O), 3.68 (s, 3 H, CH3O), 3.45–3.65 (m, 2 H, H-4), 3.23
(s, 3 H, CH3SO2O), 3.15 (m, 1 H, H-3a). ESI-HRMS: m/z
calcd for C14H18N2O6S [MH]+: 343.0958; found: 343.0963.
(7) Ronald, R. C.; Winkle, M. R. Tetrahedron 1983, 39, 2031.
(8) Several attempts to convert the alkyl hydroxy groups into
leaving groups suitable for further intramolecular O-
alkylation failed.
(9) Synthesis of Compound 11 from 10.
To a solution of 10 (2.72 mmol, 0.61 g) in THF (10 mL), in
a sealed tube under N2, Et3N (2.72 mmol, 0.38 mL), polymer
supported PPh3 (5.44 mmol, 1.81 g) and diethyl
Acknowledgment
The authors would like to gratefully acknowledge Mr. Luis Font for
his analytical work, Dr. Ana Isabel de Lucas for the preparation of
intermediates 8 and 12 and Ms. Valle Ancos for the scale-up of
compound 6.
azodicarboxylate (3.41 mmol, 0.67 mL) were added. The
reaction mixture was stirred at reflux for 16 h and then
filtered through Celite®. The Celite® pad was washed with
MeOH and the combined filtrates were evaporated. The
residue was re-dissolved in CH2Cl2 and washed with brine,
dried (Na2SO4), filtered and evaporated. The residue was
purified by flash-column chromatography on silica gel
(EtOAc) yielding compound 11 as a white foam (2.66 mmol,
0.55 g, 98%).
References
(1) Andrés, J. I.; Alcázar, J.; Alonso, J. M.; Alvarez, R. M.; Cid,
J. M.; De Lucas, A. I.; Fernández, J.; Martínez, S.; Nieto, C.;
Pastor, J.; Bakker, M. H.; Biesmans, I.; Heylen, L. I.;
Megens, A. A. Bioorg. Med. Chem. Lett. 2003, 13, 2719.
(2) Pastor, J.; Alcázar, J.; Alvarez, R. M.; Andrés, J. I.; Cid, J.
M.; De Lucas, A. I.; Díaz, A.; Fernández, J.; Lafuente, C.;
Martínez, S.; Bakker, M. H.; Biesmans, I.; Heylen, L. I.;
Megens, A. A. Bioorg. Med. Chem. Lett. 2004, 14, 2917.
(3) (a) Andrés, J. I.; Alcázar, J.; Alonso, J. M.; Alvarez, R. M.;
Bakker, M. H.; Biesmans, I.; Cid, J. M.; De Lucas, A. I.;
Fernández, J.; Font, L. M.; Hens, K. A.; Iturrino, L.;
Lenaerts, I.; Martínez, S.; Megens, A. A.; Pastor, J.;
Vermote, C. M.; Steckler, T. J. Med. Chem. 2005, 48, 2054.
(b) Andres-Gil, J. I.; Alcazar-Vaca, M. J.; Bartolome-
Nebreda, J. M.; Fernandez-Gadea, F. J.; Bakker, M. H. M.;
Megens, A. A. H. P. PCT Int. Appl. WO 2004018483, 2004;
Chem. Abstr. 2004, 140, 217631. (c) Andres-Gil, J. I.;
Fernandez-Gadea, F. J.; Alcazar-Vaca, M. J.; Cid-Nunez, J.
M.; Pastor-Fernandez, J.; Megens, A. A. H. P.; Heylen, G. I.
C. M.; Langlois, X. J. M.; Bakker, M. H. M.; Steckler, T. H.
W. PCT Int. Appl. WO 2002066484, 2002; Chem. Abstr.
2002, 137, 201298.
Representative analytical data for compound 11: syrup. 1H
NMR (400 MHz, CDCl3, 25 °C): d = 8.41 (s, 1 H, H-6), 8.27
(d, J = 5.1 Hz, 1 H, H-8), 7.59 (d, J = 5.0 Hz, 1 H, H-9), 4.72
(dd, J = 10.5 and 5.7 Hz, 1 H, H-4), 4.50 (dt, J = 11.8 and,
3.5 Hz, 1 H, H-3), 4.11–4.22 (m, 2 H, CH2OH and H-4), 3.98
(td, J = 12.2 and 5.7 Hz, 1 H, H-3a), 3.89 (d, J = 12.2 Hz, 1
H, CH2OH), 2.15 (s, 1 H, OH). ESI-HRMS: m/z calcd for
C10H10N2O3 [MH]+: 207.0764; found: 207.0759.
(10) Boulton, J. A.; McKillop, A. In Comprehensive
Heterocyclic Chemistry, Vol. 2; Katrizky, A. R.; Rees, C.
W., Eds.; Pergamon Press: Oxford, 1984, 29–65.
(11) Synthesis of Compound 14 from 13.
To a solution of 13 (16.4 mmol, 5.64 g) in THF–MeOH (8:1,
90 mL) at 0 °C NaBH4 (4.1 mmol, 1.55 g) was added
portionwise. The mixture was stirred at 0 °C for further 4 h
and then an aq sat. NH4Cl solution was added. The mixture
was extracted with CH2Cl2, dried (Na2SO4), filtered and
evaporated. The crude was purified by short open-column
chromatography on silica gel (heptane–EtOAc, 1:1). The
residue obtained (0.52 mmol, 1.5 g, 32%) was dissolved in
methyl isobutyl ketone (50 mL) and K2CO3 (11.7 mmol,
1.62 g) was added. The mixture was stirred at reflux for 4 d
and then the solvent was evaporated. The residue was
dissolved in CH2Cl2, washed with brine, dried (Na2SO4),
filtered and evaporated. The crude was purified by short
open-column chromatography on silica gel (CH2Cl2–NH3
sat. MeOH 19:1) yielding compound 14 as a colorless syrup
(2.13 mmol, 0.44 g, 41%).
(4) Baraldi, P. G.; Bigoni, A.; Cacciari, B.; Caldari, C.;
Manfredini, S.; Spalluto, G. Synthesis 1994, 1158.
(5) The absence of water during the reduction step is crucial in
order to keep the stereochemistry of both stereocenters,
otherwise a mixture of both diastereoisomers is obtained.
(6) Synthesis of Compound 6 from 5.
A solution of compound 5 (5.3 mmol, 2.5 g) in THF–H2O
(7.5/1, 85 mL) was hydrogenated at 40 psi of hydrogen in the
presence of 10% Pd/C (0.25 g) at r.t. for 24 h. Then the
catalyst was removed by filtration over Celite® and the
filtrate was concentrated and extracted with CH2Cl2. The
organic layer was separated, dried (Na2SO4), filtered and
evaporated. The residue obtained (2.36 g, 5.3 mmol, 100%)
was dissolved in THF (50 mL) and Et3N (13.25 mmol, 1.85
mL) was added. The resulting solution was stirred at reflux
for 24 h and then sat. NaHCO3 was added. The mixture was
extracted with CH2Cl2 and the organic layer was separated,
Representative analytical data for 14: syrup. 1H NMR (400
MHz, CDCl3, 25 °C): d = 8.29 (dd, J = 4.9, 2.0 Hz, 1 H, H-
7), 8.12 (dd, J = 7.7, 2.1 Hz, 1 H, H-9), 7.07 (dd, J = 7.7 and
4.9 Hz, 1 H, H-8), 4.79 (dd, J = 10.7 and 5.9 Hz, 1 H, H-4),
4.47 (dt, J = 11.8 and 4.1 Hz, 1 H, H-3), 4.28 (dd, J = 12.5
and 10.7 Hz, 1 H, H-4), 3.85–4.03 (m, 3 H, CH2OH and H-
3a), 3.26 (s, 1 H, OH). ESI-HRMS: m/z calcd for
C10H10N2O3 [MH]+: 207.0764; found: 207.0769.
Synlett 2005, No. 20, 3139–3141 © Thieme Stuttgart · New York