Microwave-assisted synthesis of 2-aminoquinolines

Article abstract of DOI:10.1016/S0040-4039(01)02242-0

An improved method for the synthesis of 2-aminoquinolines utilizing microwave-assisted synthesis is described. The process involves rapid microwave irradiation of secondary amines and aldehydes to form enamines followed by the addition of 2-azidobenzophenones with subsequent irradiation to produce the 2-aminoquinoline derivatives. Purification of the products is accomplished in a streamlined manner using solid-phase extraction techniques to produce the desired products in high yields and purity.

Full text of DOI:10.1016/S0040-4039(01)02242-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 581–583
Microwave-assisted synthesis of 2-aminoquinolines
Noel S. Wilson,* Christopher R. Sarko and Gregory P. Roth
Department of Medicinal Chemistry, Boehringer Ingelheim Pharmaceuticals, Inc., Research & Development Center,
900 Ridgebury Rd, Ridgefield, CT 06877-0368, USA
Received 25 October 2001; revised 14 November 2001; accepted 15 November 2001
Abstract—An improved method for the synthesis of 2-aminoquinolines utilizing microwave-assisted synthesis is described. The
process involves rapid microwave irradiation of secondary amines and aldehydes to form enamines followed by the addition of
2-azidobenzophenones with subsequent irradiation to produce the 2-aminoquinoline derivatives. Purification of the products is
accomplished in a streamlined manner using solid-phase extraction techniques to produce the desired products in high yields and
purity. © 2002 Elsevier Science Ltd. All rights reserved.
The heterocyclic quinoline scaffold and derivatives
occur in a large number of natural products1 and
drug-like compounds.2 While numerous synthetic
approaches have been developed for quinoline synthe-
sis, most are unsatisfactory for combinatorial library
production over a wide-range of substitutions and func-
tionalities.3 In other examples of cycloadditions,
microwave irradiation (noted as mW) has had dramatic
effects on reaction times, purities, and yields.4 We have
developed a new efficient method for generating 2-
aminoquinolines via a three component condensation
utilizing microwave irradiation as the heat source. In
this method, the initially formed triazoline intermedi-
ates undergo a thermal rearrangement and intermolecu-
lar base-catalyzed cyclocondensation5 to produce a
quinoline-based pharmacophore combinatorial library
(Scheme 1).
single-mode microwave irradiation7 (Tables 1 and 2).
Although conventional heating methods can be used to
synthesize 2-aminoquinolines, only low to moderate
yields are obtained even after prolonged heating
(entries 1–8). p-Xylene and toluene provided the best
results under thermal heating conditions (entries 1–3);
however, these solvents are poor microwave absorbers
so we investigated the use of DMF and DCE as possi-
ble solvents. In general, compounds with a high dielec-
tric constant (e.g. water and methanol) generally heat
more readily under microwave irradiation, while com-
pounds with lower dielectric constants and/or poor net
dipole moments poorly absorb microwaves (e.g. p-
xylene and dioxane).4 Direct reaction comparison
between thermal and microwave conditions, using iden-
tical stoichiometry and sealed reaction vessels (entries 8
and 9) show greatly improved yield for the microwave
example. This result may simply be due to the fact that
solvents, heated using microwave irradiation, can be
heated (or superheated) to a higher temperature which
We have found that a variety of amines, aldehydes, and
2-azidobenzophenones6 are readily converted to 2-
aminoquinolines in good to excellent yields by using
Scheme 1.
Keywords: microwave-assisted synthesis; 2-aminoquinolines; combinatorial chemistry.
* Corresponding author.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)02242-0

582
N. S. Wilson et al. / Tetrahedron Letters 43 (2002) 581–583
Table 1. Conventional heating versus microwave irradiation
Entry
R1, R2
R3, R4
R5
Temp. (°C)
Solvent
Time
Completion (%)a
1
2
3
4
5
6
7
8
5-Cl
5-Cl
5-Cl
Morpholine
Morpholine
Morpholine
H
H
H
H
H
H
H
H
H
H
H
H
Reflux
110
110
110
110
p-Xylene
Toluene
Toluene
Toluene
Toluene
DCE
DMF
DCE
DCE
DCE
4 h
6 h
24 h
6 h
24 h
24 h
24 h
10 min
8 minf
10 minf
13 minf
10 minf
52b
39c
50c
10
31
11
16
31
63
73
29
38
5-NO2,H
5-NO2,H
5-NO2,H
5-NO2,H
5-NO2,H
5-NO2,H
5-NO2,H
5-NO2,H
5-NO2,H
Cyclohexyl, Me
Cyclohexyl, Me
Cyclohexyl, Me
Cyclohexyl, Me
N-Methylpiperazine
N-Methylpiperazine
N-Methylpiperazine
N-Methylpiperazine
N-Methylpiperazine
85
150
180d
180e
180e
180e
220e
9
10
11
12
DCE
DMF
a Purity determined by LC–MS analysis of crude products (integration area @ 254 nm) unless otherwise noted.
b Reported conditions and yield by E. A. Beccalli and co-workers.5
c Purity determined by ELSD-MS analysis of crude products (integration area).
d Oil bath temperature.
e Microwave irradiation done in a PS3 Smith SynthesizerTM
f Time includes 3 min required for enamine formation.
.
Table 2. Reaction validation results
Entry
R1, R2
R3,R4
R5
Yield (%)
1
2
3
4
5
6
7
4-Me, Ph
4-Me, Ph
4-Me, Ph
4-Me, Ph
4-NO2, Ph
5-Cl,o-F Ph
4-Br,o-F Ph
Me, Bz
4-Ethoxyphenyl
4-Ethoxyphenyl
4-Ethoxyphenyl
4-Ethoxyphenyl
3,4-Dimethoxy Phenyl
2-Fluorophenyl
76
62
72
71
100
64
57
Me, 3,4-Dimethoxyphenyl
Methylisonipecotate
4-Furoylpiperazine
Pyrrolidine
Methylisonipecotate
Morpholine
3,4-Dichlorophenyl
is known as the nucleation limited boiling point8 and
such superheating may increase overall reaction rates.
Furthermore, we have noted that the purity of products
resulting from the traditional thermal reactions is also
reduced due to the presence of decomposed 2-
azidobenozphenone.
eluent to remove the impurities followed by 1% HCl/
MeOH to release the 2-aminoquinoline. While DMF
can be used in this reaction, lower yields are typically
observed (Table 1, entry 12) and the reaction workup is
significantly more complicated. The differences in yield
between entries 10 and 12 maybe due to pressure effects
in these reactions.
Optimized reaction conditions were produced by heat-
ing for 10 min in 1,2-dichloroethane (1,2-DCE) at
180°C, which includes 3 min for enamine formation
(Table 1, entry 10). The irradiated reaction mixture was
filtered through an SCX cartridge with 1,2-DCE as the
In conclusion, we have developed a simple, rapid, two-
step, one-pot method for the conversion of 2-azidoben-
zophenones into corresponding 2-aminoquinolines in
good to excellent yields using microwave irradiation.

N. S. Wilson et al. / Tetrahedron Letters 43 (2002) 581–583
583
The compounds were further purified using simple SPE
purification techniques. Overall we found that this
approach accelerated the overall reaction 24 fold. The
versatility of this methodology can be extended to
develop a streamlined approach to 2-aminoquinoline
libraries in a combinatorial fashion.
9989; (b) Michael, J. P. Nat. Prod. Rep. 1997, 14, 605; (c)
Morimoto, Y.; Matsuda, F.; Shirahama, H. Synlett 1991,
202.
2. Campbell, S. F.; Hardstone, J. D.; Palmer, M. J. J. Med.
Chem. 1988, 31, 1031.
3. (a) Meth-Cohn, O.; Taylor, D. L. Tetrahedron 1995, 51,
12869; (b) Adams, D. R.; Dominguez, J. N.; Perez, J. A.
Tetrahedron Lett. 1983, 24, 517; (c) Cho, C. S.; Oh, B. H;
Shim, S. C. Tetrahedron Lett. 1990, 31, 1499; (d) Zhou, L.;
Zhang, Y. J. Chem. Soc., Perkin Trans. 1 1998, 2899; (e)
Larock, R. C.; Kero, M.-Y. Tetraheron Lett. 1991, 32, 569;
(f) Zhou, L.; Tu, S.; Shi, D.; Dai, G.; Chen, W. Synthesis
1988, 2899; (g) Larock, R. C.; Babue, S. Tetrahedron Lett.
1987, 28, 5291.
4. For reviews on microwave chemistry see: (a) Listrom, P.;
Tierney, J.; Wathey, B.; Westman, J. Tretrahedron Lett.
2001, 57, 9225; (b) Caddick, S. Tetrahedron 1995, 51,
10403; (c) Strauss, C. R.; Trainor, R. W. Aust. J. Chem.
1995, 48, 1665; (d) Galema, S. A. Chem. Soc. Rev. 1997,
26, 233; (e) Loupy, A.; Petit, A.; Hamelin, J.; Texier-Boul-
let, F.; Jacquault, P.; Malte, D. Synthesis 1998, 1213.
5. Beccalli, E. A; Erba, E.; Gelmi, M. L.; Pocar, D. Bull. J.
Chem. Soc., Perkin Trans. 1 1996, 1359–1364.
6. The azide was prepared by adding NaNO2 (2 equiv.) to a
suspension 2-amino-5-nitrobenzophenone (1 equiv.) in
TFA (3.5 mL) @ 0°C. After stirring for 20 min NaN3 (3
equiv.) was added (N2 evolved). The mixture was stirred
for 20 min then quenched by addition of ice/H2O. Water is
added until a light yellow suspension formed, the suspen-
sion filtered, washed with water, and dried under vacuum.
7. Personal Chemistry, Inc., 25 Birch Street, Building C,
Typical experimental procedure
In a typical procedure, the enamine was prepared in
situ by adding N-methylcyclohexylamine (1 mmol) and
phenylacetaldehyde (1.1 mmol) to a Smith Process
VialTM (glass vessel) containing 4 mL of DCE. The vial
was sealed and the mixture was heated in the Smith
SynthesizerTM microwave at 180°C for 3 min, cooled to
room temperature, and added to a second capped
Smith
Process
VialTM
containing
2-azido-5-
nitrobenzophenone9 (0.8 mmol). The mixture was then
heated a second time in the microwave at 180°C for 7
min and cooled to room temperature. The crude mix-
ture was purified by filtering through a Varian SCX
cartridge with DCE or DCM as the eluent to remove
the impurities followed by 1% HCl/MeOH to release
the 2-aminoquinoline. The 1% HCl/MeOH fractions
are combined and the solvent removed on a rotary
evaporator to furnish the desired material as a solid.
Acknowledgements
Suite
104,
Milford,
MA
01757,
USA
The authors would like to thank Dr. Heewon Lee and
George Lee for their analytical assistance and from
Personal Chemistry, Inc, Bob Beaudoin and Andreas
Hoel for their technical assistance.
(www.personalchemistry.com)
8. Baghurst, D. R.; Mingos, D. M. P. J. Chem. Soc., Chem.
Commun. 1992, 674.
9. Although no safety issues were encountered when heating
2-azido-5-nitrobenzophenone
derivatives
in
the
microwave, the authors stress safety precautions should be
taken whenever heating azides to elevated temperatures in
order to avoid the possibility of explosion.
References
1. (a) Katrititzy, A. R.; Arend, M. J. Org. Chem. 1998, 63,