Efficient and versatile synthesis of 2,3-Dialkylimidazo[4,5-b]quinolin-9- ols by microwave-assisted one-pot Beckmann rearrangement

Article abstract of DOI:10.1055/s-0028-1083197

A direct microwave-assisted one-pot Beckmann rearrangement of 3-acyl-2-(alkylamino)quinolin-4-(1H)-ones in ethanol-pyridine (2:1) provides 2,3-dialkylimidazo[4,5-b]quinolin-9-ols as major products along with 2-alkyl-N-alkyloxazolo[4,5-c]quinolin-4-amines and 3-alkyl-N-alkylisooxazolo[4, 5-c]quinolin-4-amines as minor products. Reactions of 3-acylquinoIin-4-(1H)- ones containing secondary amine substituent at C-2 give 2-alkyloxazolo[5,4-b] quinolin-9-ols as major products via elimination of the secondary amine group. A mechanism proposed for the formation of Beckmann rearrangement products involves initial generation of a nitrilium ion intermediate, which is trapped either by the adjacent nitrogen of the γ-amino group to form imidazoquinolinols or by the oxygen of γ-hydroxy group of the tautomeric form of the ketoxime to form oxazoloquinolinamines. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0028-1083197

PAPER
3569
Efficient and Versatile Synthesis of 2,3-Dialkylimidazo[4,5-b]quinolin-9-ols by
Microwave-Assisted One-Pot Beckmann Rearrangement
M
icrowave-Assis
o
te
d
D
irect
O
ne-Pot
H
B
eckmann Rearra
y
ngement un Hwang,a,b Eun Bok Choi,a Hyeon Kyu Lee,a Hee Cheol Yang,a Bong Young Chung,b Chwang Siek Pak*a
a
Korea Research Institute of Chemical Technology, Yusung-Ku Jang-Dong 100, Taejeon 305-600, Korea
Fax +82(42)8600307; E-mail: cspak@krict.re.kr
b
Department of Chemistry, Korea University, Anam-Dong Seongbuk-Gu, Seoul 136-701, Korea
Received 27 June 2008; revised 6 August 2008
oximes were prepared by the reaction of 2-alkylthio-3-
acylquinolinones with hydroxylamine hydrochloride in
ethanol–pyridine (2:1) mixture at room temperature.6 In
contrast to that of 2-alkylthio-3-acylquinolinones, oxima-
Abstract: A direct microwave-assisted one-pot Beckmann rear-
rangement of 3-acyl-2-(alkylamino)quinolin-4-(1H)-ones in etha-
nol–pyridine (2:1) provides 2,3-dialkylimidazo[4,5-b]quinolin-9-
ols as major products along with 2-alkyl-N-alkyloxazolo[4,5-
c]quinolin-4-amines and 3-alkyl-N-alkylisooxazolo[4,5-c]quinolin- tion of 2-alkylamino-3-acylquinolinones 17 is a formida-
4-amines as minor products. Reactions of 3-acylquinolin-4-(1H)-
ones containing secondary amine substituent at C-2 give 2-alkylox-
ble task (Equation 1). Initial attempts to promote reaction
of 1a with hydroxylamine hydrochloride in refluxing eth-
azolo[5,4-b]quinolin-9-ols as major products via elimination of the
anol–pyridine (2:1) failed to generate the oxime even after
secondary amine group. A mechanism proposed for the formation
three days and led to complete recovery of 1a. Modifica-
of Beckmann rearrangement products involves initial generation of
tion of the reaction conditions, such as using 50% aqueous
hydroxylamine8 without base or in ethanol in the presence
of different kinds of bases (e.g., triethylamine,9 sodium
acetate,10 potassium carbonate,11 sodium hydroxide12) did
not result in any reaction of 1a. Furthermore, a solid state
reaction using FeCl3·6H2O13 was also unsuccessful. Ap-
plication of another procedure for oximation14 using n-
butylamine as a base to form the oxime salt did not pro-
duce the desired product.
a nitrilium ion intermediate, which is trapped either by the adjacent
nitrogen of the g-amino group to form imidazoquinolinols or by the
oxygen of g-hydroxy group of the tautomeric form of the ketoxime
to form oxazoloquinolinamines.
Key words: microwave, one-pot Beckmann rearrangement, cy-
clization, imidazoquinolinol, oxazoloquinoline
Substances possessing the imidazoquinoline1 and
oxazoloquinoline2 skeletons exhibit novel biological ac-
tivities. Imidazolo[4,5-b]quinoline derivatives have been
probed as nitric oxide synthase (NOS) inhibitors in the
context of potential use in the treatment of acute inflam-
matory disorders including septic shock, hemorrhagic
shock, transplant rejection, and chronic inflammatory dis-
orders such as inflammatory bowel disease, asthma,
arthritis, Alzheimer’s disease, pain, and ischemia-reperfu-
sion injury.3 Oxazolo[4,5-c]quinolin-4-amine derivatives
serve as modulators of cytokine production, which act as
the immunomodulator and inducer of the biosynthesis of
cytokines, particularly interferon-a (IFN-a) and TNF-a.
As a result, these substances are potentially useful in the
treatment of cancer and viral diseases.2 In addition, imida-
zoquinolines and oxazoloquinolines have been explored
as novel immunostimulant drugs.4 The previous methods
developed for the preparation of imidazoquinolines and
oxazoloquinolines are tedious and start with substances
that are difficult to secure. In connection with a biological
screening program, we required a number of modified im-
idazoloquinoline and oxazoloquinoline derivatives. We
have previously described the synthesis of oxazoloquino-
lines from 2-alkylthio-3-acylquinolinones via Beckmann
rearrangement of the corresponding oxime derivatives us-
ing indium(III) chloride as a catalyst.5 In this case, the
OH
O
N
O
O
conventional
methods
N
H
NH
N
H
NH
1a-oxime
1a
Equation 1 Attempted oximation of 2-alkylamino-3-acylquinoli-
nones 1 using conventional methods failed
Since microwave irradiation is known to effectively ini-
tiate oximation,15 this technique was applied in an effort
to overcome the drawbacks associated with the use of
conventional methods16 (Table 1). To our knowledge no
report has been published describing attempts to employ
microwave irradiation for the one-pot synthesis of imida-
zo- and oxazoloquinolines in the absence of heteroge-
neous catalysts.
Although one-pot Beckmann rearrangements using sol-
vent-free microwave irradiation in the presence of cata-
lysts such as alumina,17 FeCl3·6H2O,13 HY-Zeolite,
NaHSO4·SiO2, silica chloride have been described,18 ap-
plications of these reaction conditions to 1a was not suc-
cessful. Under microwave condition in the absence of
solvent (Method D) and in the presence of FeCl3·6H2O,
reaction of 1a with hydroxylamine hydrochloride pro-
ceeded smoothly to completion. The highly polar, water
soluble product generated in this process in a yield of 43%
SYNTHESIS 2008, No. 22, pp 3569–3578
x
x.
x
x
.
2
0
0
8
Advanced online publication: 23.10.2008
DOI: 10.1055/s-0028-1083197; Art ID: F14408SS
© Georg Thieme Verlag Stuttgart · New York

3570
B. H. Hwang et al.
PAPER
Table 1 Optimization of Microwave Reaction Condition of 3-Acetyl-2-(propylamino)quinolin-4(1H)-one (1a)
Catalyst
Solvent
EtOH
EtOH
EtOH
EtOH
–
Base
Temp (°C)
130
Time (h)
0.5
Method (NH2OH, equiv)a
A (1.2)
Yield (%)
73
–
pyridine
–
pyridine
60
2.5
A (1.0)
20b
–
pyridine
130
2.0
B (1.2)
NRc
NR
–
–
–
–
–
–
–
130
2.0
C (1.2)
Basic Al2O3
FeCl3·6H2O
HY-Zeolite
NaHSO4·SiO2
silica gel chloride
100
0.5
A (1.2)
NR
d
–
25
0.5
D (1.2)
–
–
130
0.5
D (1.3)
NR
NR
NR
130
0.5
D (1.3)
–
130
0.5
D (1.3)
a A: NH2OH·HCl, EtOH–pyridine = 2:1; B: 50% aq NH2OH, EtOH–pyridine = 2:1; C: 50% aq NH2OH, EtOH; D: NH2OH·HCl, solvent-free.
b More than 80% of starting material remained.
c NR: no reaction.
d Deacetylated product, 2-(propylamino)quinolin-4(1H)-one, was obtained in a yield of 43%.
was identified as the deacylated quinolinone, 2-(propyl- alkylamino-3-acylquinolinones 1 were subjected to mi-
amino)quinolin-4(1H)-one. This substance is identical crowave reaction with hydroxylamine in order to prepare
with the product obtained by refluxing the same substrate 2,3-dialkylimidazo[4,5-b]quinolin-9-ols 2. It was found
in aqueous trifluoroacetic acid.
that these processes take place in moderate to good yields
(Table 2).
Instead of the expected oxime, microwave irradiation
(Method A) of a mixture of 1a and hydroxylamine hydro- The mixtures obtained from these reactions display simi-
chloride in ethanol–pyridine (2:1) leads to the formation lar TLC patterns exhibiting fluorescence for isooxazolo-
of a mixture of imidazoquinolinol 2a, oxazoloquinoline quinolinols 4. Selected reaction mixtures (entries 1, 3, 5,
3a, and isooxazoloquinoline 4a in 75, 11, and 8% yield, 6, 10, 13) were analyzed, and three isomeric products 2, 3,
respectively (Scheme 1).
4 were identified (see Experimental). It was not sufficient
to discern the structural identity of the isomeric products
by using spectroscopic analysis. In order to identify struc-
tures unambiguously, X-ray crystallographic analysis was
performed with isomeric products 2m, 3m, and 4m
(Figures 1– 3) derived from substrate 1m. The formation
of imidazoquinolinol 2a and oxazoloquinoline 3a in the
reaction of 1a with hydroxylamine can be explained by a
mechanism involving a nitrilium ion intermediate. Prefer-
ential addition of the more nucleophilic nitrogen of the 2-
amino group to the nitrilium ion leads to the production of
2a while addition of oxygen of 4-hydroxyl group affords
3a. These cyclization processes can occur either by way of
the trapping reactions described above or following for-
mation of an amide, the typical Beckmann rearrangement
product. Examples of intramolecular cyclization taking
place in the course of Beckmann rearrangement have been
This reaction is complete within 0.5 hour and the formed
imidazoquinolinol 2a can be simply separated by filtra-
tion. The filtrate contained the other products 3a and 4a,
which are then separated by preparative TLC. Since 3a
and 4a are not well resolved, only analytical samples can
be obtained by preparative TLC. The one-pot Beckmann
rearrangement of 1a does not take place (even after 2 h) to
give 2a and 3a when 50% aqueous NH2OH (Methods B,
C) instead of NH2OH·HCl is used. It is likely that HCl
plays an important role in the process. When the reaction
temperature is lowered to 60 °C, the reaction proceeds
sluggishly, and more than 80% of starting material re-
mained even after 2.5 hours. To our knowledge no previ-
ous attempt has been made to employ microwave
irradiation conditions for a one-pot synthesis of imida-
zoles. To probe the scope of this methodology, various 2-
O
O
N
O
O
OH
N
N
µW
N
N
+
NH2OH⋅HCl
+
+
N
H
NH
NH
NH
N
N
1a
2a
3a
4a
8%
75%
11%
Scheme 1 Microwave reaction products of 3-acetyl-2-(propylamino)quinolin-4(1H)-one (1a) with hydroxylamine hydrochloride
Synthesis 2008, No. 22, 3569–3578 © Thieme Stuttgart · New York

PAPER
Microwave-Assisted Direct One-Pot Beckmann Rearrangement
3571
Table 2 One-pot Beckmann Rearrangement Products Using microwave Reaction Condition
R1
N
O
O
O
OH
O
R1
R2
N
R1
R2
N
Z
µW
R1
+
+
NH2OH⋅HCl
EtOH–py
R2
N
N
R3
N
H
N
R3
N
X
X
N
R3
N
X
X
R3
4
1
2 or 5
3
Entry
1
Substituents of 1
Product 2 or 5a
X
R1
R2
H
R3
Z
Time (min) Yield (%)b Mp (°C)
1
2
1a
1b
1c
H
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
n-Pr
n-Pr
i-Pr
N
N
N
N
N
N
N
N
N
N
N
N
N
N
O
O
O
O
O
40
20
20
30
20
20
20
20
40
20
30
40
30
20
20
20
120
30
30
75
70
44
47
75
88
88
83
74
48
58
59
58
62
49
48
67
47
68
307–310
232–233
395–397
242–245
162–163
277–279
279–280
311–312
341–342
294–295
315–318
280–283
253–255
282–284
302–304
297–298
211–213
296–297
301–302
8-Me
5,7-Me2
8-Me
5,8-Cl2
6-t-Bu
6-t-Bu
6-MeO
7,8-Cl2
6-t-Bu
H
H
3
H
4
1d
1e
H
allyl
allyl
c-Bu
n-C5H11
Me
5
H
6
1f
H
7
1g
1h
1i
H
8
H
9
H
Me
10
11
12
13
14
15
16
17
18
19
1j
H
(2,2-Ph2)-3-Pr
1k
1l
H
Ph
8-Me
8-Cl
H
H
Ph
1m
1n
1oc
1pd
1qe
1rg
1sh
H
i-Pr
i-Bu
Me
Me
Ph
H
H
Me
Me
Ph
Me
Me
8-Me
H
morpholinof
morpholinof
morpholinof
5,8-Cl2
H
Me
Me
a See experimental.
b Isolated yields.
c 3-Acetyl-2-(dimethylamino)quinolin-4(1H)-one.
d 3-Acetyl-2-(dimethylamino)-5-methylquinolin-4(1H)-one.
e 3-Benzoyl-2-morpholinoquinolin-4(1H)-one.
f N(R2R3) = morpholino.
g 3-Acetyl-5,8-dichloro-2-morpholinoquinolin-4(1H)-one.
h 3-Acetyl-2-morpholinoquinolin-4(1H)-one. These secondary amino group substituted quinolinones were used as substrates.
observed in the reactions of 2¢-hydroxyacetophenone acetylquinolinones substituted with primary amino
oxime,19 2¢-amino- and 2¢-mercaptoacetophenone oxime, groups at C-2 (entries 1–14) underwent Beckmann rear-
which form the corresponding benzoxazole, benzimida- rangement involving the amine nitrogen as a nucleophile,
zole, and benzothiazole, respectively.19d Cyclization of those with secondary C-2 amino groups (entries 15–18)
amides is also known to form either fused oxazoles, such react via elimination of the amine group.
as oxazolopyridine,20 benzoxazole,21 naphthooxazole22
Whereas the reaction of the quinolinone substituted with
a dimethylamino group (entries 15, 16) proceeds to com-
from the corresponding 2¢-hydroxyanilides, or fused imi-
dazoles, such as imidazopyridine,23 imidazopyrimidine24
pletion in 20 minutes, conversion of the morpholino ana-
from the corresponding 2¢-aminoanilides. While 3-
logue 1q requires a prolonged reaction time (2 h). In the
Synthesis 2008, No. 22, 3569–3578 © Thieme Stuttgart · New York

3572
B. H. Hwang et al.
PAPER
Figure 1 X-ray crystal structure of 5-chloro-2-ethyl-3-isopropyl-
3H-imidazo[4,5-b]quinolin-9-ol (2m) at the 50% probability level
Figure 3 X-ray crystal structure of 6-chloro-3-ethyl-N-isopro-
pylisoxazolo[4,5-c]quinolin-4-amine (4m) at the 50% probability
level
morpholinoisoxazolo[4,5-c]quinoline (4s) are produced
in 68, 6, and 12% yield, respectively (Scheme 2). In this
process, the morpholine group was eliminated after in-
tramolecular trapping of nitrilium ion intermediate gener-
ated during rearrangement as depicted in Scheme 3.
Although an amide product was not isolated, it is possible
that it is formed by a normal Beckmann rearrangement
and then cyclizes (see above).20–24Although amide prod-
uct was not isolated under the reaction condition, another
possibility is that cyclization might take place after forma-
tion of amide as previously noted.20–24
Figure 2 X-ray crystal structure of 6-chloro-2-ethyl-N-isopropyl-
oxazolo[4,5-c]quinolin-4-amine (3m) at the 50% probability level
In summary, the results of the study described above dem-
case of 1s, 2-methyloxazolo[5,4-b]quinolin-9-ol (5s) as a onstrate that by employing microwave irradiation along
major product and two isomeric products, 2-methyl-4- with normal oximation reaction conditions, a wide variety
morpholinooxazolo[4,5-c]quinoline (3s), and 3-methyl-4- of imidazoquinoline and oxazoloquinoline products can
OH
O
N
O
O
µW
N
N
O
NH2OH⋅HCl
+
O
+
+
N
N
H
1s
N
N
N
N
N
4s
O
3s
O
O
5s
6%
12%
68%
Scheme 2 Elimination of morpholine, secondary amino group, in the reaction of 1s
3s
– H+
O
O
O
O
N
µW
+
H+
– H2O
OH
N
H2O
+ NH2OH⋅HCl
O
N
+
N
N
H
N
N
N
N
H
N
H
N
N
H
O
O
O
O
1s
O
O
O
H
H
N
N
5s
H
N
+
N
N
– H+
N
O
N
H
N
H
N
H
OH
OH
O
O
O
O
Scheme 3 Plausible Beckmann rearrangement mechanism for reaction of 3-acetyl-2-morpholinoquinolin-4(1H)-one (1s)
Synthesis 2008, No. 22, 3569–3578 © Thieme Stuttgart · New York

PAPER
Microwave-Assisted Direct One-Pot Beckmann Rearrangement
3573
evaporation of CH2Cl2 under vacuum, the residue was subjected to
preparative TLC (silica gel) with hexane–EtOAc (2:1) as eluent to
afford oxazoloquinoline 3a (11 mg, 11%) as a waxy solid and isox-
azoloquinoline 4a (7.7 mg, 8%) as a white solid.
be prepared conveniently starting with 2-monoalkylami-
no-3-acylquinolin-4-ones. In this process, the C-2 amine
group is incorporated into the fused heterocycle products.
In contrast, microwave promoted reactions of 2-dialkyl-
amino-3-acylquinolin-4-ones take place to yield elimina-
tion products.
2-Methyl-3-propyl-3H-imidazo[4, 5-b]quinolin-9-ol (2a)
Yield: 75%; olive green solid; mp 307–310 °C; Rf = 0.29 (hexane–
EtOAc, 1:1).
1H NMR (CD3OD): d = 8.41 (d, J = 8.1 Hz, 1 H), 7.85–7.82 (m, 2
H), 7.49 (dt, J = 2.3, 8.1 Hz, 1 H), 4.40 (t, J = 7.8 Hz, 2 H), 1.97
(sext, J = 7.8 Hz, 2 H), 1.12 (t, J = 7.5 Hz, 3 H).
13C NMR (DMSO-d6): d = 129.723, 126.612, 149.952, 149.112,
118.752, 121.009, 103.617, 48.118, 22.543, 11.425.
1H NMR spectra were recorded on a Bruker Avance 300 (300 MHz)
spectrometer and 13C NMR spectra were recorded on a Bruker
Avance 500 (125 MHz) spectrometer, unless otherwise specified, in
CDCl3 solution using TMS as internal standard. Melting points
were determined on a MPA100 (SRS) and Thomas-Hoover Unimelt
capillary apparatus and are uncorrected. Mass spectra were obtained
on a Shimadzu GC/MC-QP 1000 spectrometer. High-resolution
mass spectra were obtained on a VGQUATTRO triple quadrupole
tandem Micromass Autospec Mass spectrometer with electron
beam energy of 70 eV (EI). Column chromatography was per-
formed with Merck Kieselgel 60 (230–400 mesh). Analytical TLC
analyses were performed on precoated silica gel plates (0.25 mm
60F-254E, Merck). X-ray crystal structure analyses were performed
on a Bruker SMART Apex II X-ray Diffractometer. Reflection data
were collected on a Bruker SMART Apex II X-ray Diffractometer
with Mo tube and Graphite-Monochromator (50 KV, 30 mA). Cell
parameters were determined and refined by Bruker SHELXTL pro-
gram. All microwave reactions were carried out in 5 mL sealed
glass tubes in a focused monomode microwave oven (‘Emrys cre-
ator’ by Personal Chemistry AB company). Microwave oven condi-
tions were set up at a temperature of 130 °C with a maximum power
level of 300 W during a reaction time of 20–30 min.
MS (EI): m/z = 241 (M+), 226, 213, 199, 130, 114, 102, 76.
HRMS (EI): m/z calcd for C14H15N3O: 241.1215; found: 241.1218.
2,5-Dimethyl-3-propyl-3H-imidazo[4,5-b]quinolin-9-ol (2b)
Yield: 70%; mp 232–233 °C; Rf = 0.14 (hexane–EtOAc, 1:1).
1H NMR (CD3OD): d = 8.41 (d, J = 8.1 Hz, 1 H), 7.85–7.82 (m, 2
H), 7.49 (dt, J = 2.3, 8.1 Hz, 1 H), 4.40 (t, J = 7.8 Hz, 2 H), 1.97
(sext, J = 7.8 Hz, 2 H), 1.12 (t, J = 7.5 Hz, 3 H).
13C NMR (DMSO-d6): d = 148.002, 134.814, 130.272, 127.212,
159.521, 149.426, 119.211, 102.924, 48.117, 22.532, 16.502,
11.411, 7.942.
MS (EI): m/z = 255 (M+), 246, 233, 219, 76.
HRMS (EI): m/z calcd for C15H17N3O: 255.1372; found: 255.1316.
3-Isopropyl-2,6,8-trimethyl-3H-imidazo[4,5-b]quinolin-9-ol
All the reagent grade chemicals, purchased from Aldrich, Fluka,
Merck, and TCI chemical company, were used without further pu-
rification. All the organic solvents were obtained from Duksan,
Samchun, SK chemical company. THF was refluxed over sodium in
the presence of benzophenone and distilled prior to use. CH2Cl2 was
dried by distilling over CaH2. NMR solvents were purchased from
Cambridge Isotope Laboratories, Inc.
(2c)
Yield: 44%; white solid; mp 395–397 °C; Rf = 0.05 (hexane–
EtOAc, 1:1).
1H NMR (CD3OD): d = 7.47 (s, 1 H), 6.92 (s, 1 H), 5.19 (d, J = 7.8
Hz, 1 H), 4.63–4.56 (m, 1 H), 2.77 (s, 3 H), 2.71 (s, 3 H), 2.44 (s, 3
H), 1.35 (s, 3 H), 1.32 (s, 3 H).
13C NMR (CD3OD): d = 161.748, 149.544, 138.381, 131.617,
125.730, 124.644, 124.384, 111.038, 42.340, 23.408, 21.824,
21.202, 14.730.
X-ray Crystal Structure Determination25
Single-crystal X-ray diffraction data were collected at 296K on a
Bruker SMART APEX II CCD-based diffractometer with graphite-
monochromated MoKa radiation (l = 0.71073A).26 The reflection
data were collected as F and w scan frames with of 0.5 °/frame and
exposure time of 10 s/frame. Cell parameter were determined and
refined by SMART program.26 Among 15241 collected reflections
3589 were unique (Rint = 0.0533). Data reductions were performed
using SAINT software.26 Multiscan absorption correction was ap-
plied with SADABS program.26 The structures of the compounds
were solved by using direct methods and refined by full matrix
least-squares methods using SHELXTL program package27 with
anisotropic thermal parameters for all nonhydrogen atoms; all the
hydrogen atoms were put into calculated positions with the isotropic
thermal parameters.
MS (EI): m/z = 269 (M+), 254, 227, 212, 197, 158, 142, 127, 84, 58.
HRMS (EI): m/z calcd for C14H11Cl2N3O: 269.1528; found:
269.1520.
3-Allyl-2,5-dimethyl-3H-imidazo[4,5-b]quinolin-9-ol (2d)
Yield: 47%; brown solid; mp 242–245 °C; Rf = 0.35 (hexane–
EtOAc, 1:1).
1H NMR (CD3OD): d = 8.29 (d, J = 8.6 Hz, 1 H), 7.70 (d, J = 7.0
Hz, 1 H), 7.45 (t, J = 8.2 Hz, 1 H), 6.20–6.04 (m, 1 H), 5.44–5.35
(m, 1 H), 5.29–5.26 (m, 2 H), 2.87 (s, 3 H), 2.76 (s, 3 H).
13C NMR (DMSO-d6): d = 159.533, 152.432, 149.372, 148.123,
134.842, 132.772, 130.211, 127.242, 119.223, 115.916, 102.927,
49.112, 16.389.
One-Pot Microwave Reaction of 1a with Hydroxylamine Hy-
drochloride; 2-Methyl-3-propyl-3H-imidazo[4,5-b]quinolin-9-
ol (2a); Typical Procedure
MS (EI): m/z = 253 (M+), 238, 212, 171, 144, 116, 89, 63.
HRMS (EI): m/z calcd for C15H15N3O2: 253.1210; found: 253.1210.
A solution of 3-acetyl-2-(propylamino)quinolin-4(1H)-one (1a; 98
mg, 0.4 mmol) in a mixture of EtOH (3 mL) and pyridine (1.5 mL)
containing NH2OH·HCl (42 mg, 0.6 mmol) in a pressure vessel (7
mL) was irradiated in a microwave oven at 130 °C for 30 min. The
solvent was removed under vacuum and CH2Cl2 (30 mL) was added
to the residue. The precipitate 2a was filtered and washed with
CH2Cl2 (2 × 15 mL) and dried under vacuum to give 73 mg (75%)
of an olive green solid. The filtrate was sequentially washed with aq
5% HCl (30 mL), H2O (50 mL) and sat. aq NaHCO3 (30 mL). After
3-Allyl-5,8-dichloro-2-methyl-3H-imidazo[4,5-b]quinolin-9-ol
(2e)
Yield: 75%; yellow solid; mp 162–163 °C; Rf = 0.17 (hexane–
EtOAc, 1:1).
1H NMR (CD3OD): d = 7.57 (d, J = 8.7 Hz, 1 H), 7.23 (d, J = 8.4
Hz, 1 H), 6.06–5.96 (m, 1 H), 5.51 (d, J = 17.7 Hz, 1 H), 5.36 (d,
J = 10.2 Hz, 1 H), 4.12 (d, J = 3.8 Hz, 2 H), 2.19 (s, 3 H).
Synthesis 2008, No. 22, 3569–3578 © Thieme Stuttgart · New York

3574
B. H. Hwang et al.
PAPER
13C NMR (CD3OD): d = 167.730, 153.963, 151.372, 145.827,
134.498, 130.842, 129.986, 127.792, 123.980, 117.535, 113.238,
106.814, 43.966, 12.161.
1H NMR (CD3OD): d = 8.15 (s, 1 H), 7.65 (d, J = 8.4 Hz, 1 H), 7.47
(d, J = 8.4 Hz, 1 H), 7.33–7.19 (m, 10 H), 4.12 (s, 2 H), 2.18 (s, 3
H), 2.09 (s, 3 H), 1.38 (s, 9 H).
MS (EI): m/z = 307 (M+), 292, 292, 280, 268, 253, 185, 167, 149,
111, 97, 83, 71.
13C NMR (CD3OD): d = 147.757, 130.276, 129.572, 128.556,
127.718, 53.203, 35.651, 31.942, 27.234.
HRMS (EI): m/z calcd for C14H11Cl2N3O: 307.0279; found:
MS (EI): m/z = 449 (M+), 286, 268, 252, 240, 181, 103, 57.
307.0254.
HRMS (EI): m/z calcd for C30H31N3O: 449.2467; found: 449.2468.
7-(tert-Butyl)-3-cyclobutyl-2-methyl-3H-imidazo[4,5-b]quino-
lin-9-ol (2f)
Yield: 88%; white solid; mp 277–279 °C; Rf = 0.12 (hexane–
EtOAc, 1:1).
1H NMR (CD3OD): d = 8.41 (s, 1 H), 7.92 (dd, J = 11.4, 9.0 Hz, 2
H), 5.22 (quint, J = 8.4 Hz, 1 H), 2.87–3.05 (m, 2 H), 2.91 (s, 3 H),
2.76–2.68 (m, 2 H), 2.15–2.01 (m, 2 H), 1.44 (s, 9 H).
13C NMR (DMSO-d6): d = 8.41 145.440, 50.006, 34.509, 31.044,
28.415, 14.874, 13.837.
2-Methyl-3-phenyl-3H-imidazo[4,5-b]quinolin-9-ol (2k)
Yield: 58%; white solid; mp 315–318 °C; Rf = 0.24 (hexane–
EtOAc, 1:1).
1H NMR (CD3OD): d = 8.41 (d, J = 8.2 Hz, 1 H), 7.72–7.69 (m, 3
H), 7.62–7.56 (m, 4 H), 7.56–7.31 (m, 1 H), 2.35 (s, 3 H).
13C NMR (CDCl3): d = 158.798, 151.641, 150.399, 142.912,
131.855, 128.567, 122.147, 121.476, 120.284, 119.593, 48.808,
21.660, 20.862, 12.945.
MS (EI): m/z = 275 (M+), 205, 199, 138, 102, 77.
MS (EI): m/z = 309 (M+), 294, 281, 266, 240, 133, 119, 55.
HRMS (EI): m/z calcd for C17H13N3O: 275.1059; found: 275.1043.
HRMS (EI): m/z calcd for C19H23N3O2: 309.1841; found: 309.1844.
2,5-Dimethyl-3-phenyl-3H-imidazo[4,5-b]quinolin-9-ol (2l)
Yield: 59%; white solid; mp 280–283 °C; Rf = 0.35 (hexane–
EtOAc, 1:1).
1H NMR (CD3OD): d = 8.32 (d, J = 8.4 Hz, 1 H), 7.79–7.66 (m, 6
H), 7.45 (d, J = 9.3 Hz, 1 H), 2.69 (s, 3 H), 2.58 (s, 3 H).
13C NMR (DMSO-d6): d = 159.542, 149.746, 148.127, 130.224,
129.421, 128.036, 127.248, 121.412, 121.018, 119.218, 118.572,
16.447, 7.637.
7-(tert-Butyl)-2-methyl-3-pentyl-3H-imidazo[4,5-b]quinolin-9-
ol (2g)
Yield: 88%; white-green solid; mp 279–280 °C; Rf = 0.07 (hexane–
EtOAc, 1:1).
1H NMR (CD3OD): d = 8.41 8.43 (s, 1 H), 7.77 (d, J = 8.7 Hz, 1 H),
7.62 (d, J = 8.7 Hz, 1 H), 4.19 (t, J = 7.2 Hz, 1 H), 2.54 (s, 3 H),
1.83–1.75 (m, 2 H), 1.41–1.37 (m, 4 H, s, 9 H), 0.90 (t, J = 7.2 Hz,
3 H).
13C NMR (DMSO-d6): d = 145.429, 142.976, 130.696, 126.787,
119.892, 113.412, 34.463, 31.044, 28.135, 27.688, 21.833, 13.827,
11.592.
MS (EI): m/z = 289 (M+), 275, 219, 199, 116, 77.
HRMS (EI): m/z calcd for C18H15N3O2: 289.1215; found: 289.1208.
MS (EI): m/z = 325 (M+), 310, 296, 269, 254, 240, 115, 66.
5-Chloro-2-ethyl-3-isopropyl-3H-imidazo[4,5-b]quinolin-9-ol
(2m)
Yield: 58%; white solid; mp 253–255 °C; Rf = 0.37 (hexane–
HRMS (EI): m/z calcd for C20H27N3O: 325.2154; found: 325.2158.
EtOAc, 1:1).
7-Methoxy-2,3-dimethyl-3H-imidazo[4,5-b]quinolin-9-ol (2h)
Yield: 83%; white solid; mp 311–312 °C; Rf = 0.06 (CH2Cl2–
MeOH, 20:1).
1H NMR (CD3OD): d = 7.81 (d, J = 2.7 Hz, 1 H), 7.61 (d, J = 9.0
Hz, 1 H), 7.30 (d, J = 9.0 Hz, 1 H), 3.91 (s, 3 H), 3.79 (s, 3 H), 2.55
(s, 3 H).
13C NMR (DMSO-d6): d = 154.253, 140.371, 121.243, 120.992,
119.256, 55.267, 29.892, 13.102.
MS (EI): m/z = 243 (M+), 228, 200, 117, 63, 56.
1H NMR (CD3OD): d = 8.42 (d, J = 8.6 Hz, 1 H), 7.80 (d, J = 7.2
Hz, 1 H), 7.30 (t, J = 8.4 Hz, 1 H), 4.85–4.80 (m, 1 H), 3.16 (q,
J = 7.5 Hz, 2 H), 2.05 (s, 3 H), 1.92 (s, 3 H), 1.46 (t, J = 7.5 Hz, 3
H).
13C NMR (CD3OD): d = 158.798, 151.641, 150.399, 142.912,
131.855, 128.567, 122.147, 121.476, 120.284, 119.593, 48.808,
21.660, 20.862, 12.945.
MS (EI): m/z = 289 (M+), 274, 262, 247, 233, 189, 172, 105, 91, 77,
65.
HRMS (EI): m/z calcd for C13H13N3O2: 243.1008; found: 243.1006.
HRMS (EI): m/z calcd for C15H16ClN3O: 289.0982; found:
289.0981.
5,6-Dichloro-2,3-dimethyl-3H-imidazo[4,5-b]quinolin-9-ol (2i)
Yield: 74%; dark brown solid; mp 341–342 °C; Rf = 0.13 (hexane–
EtOAc, 1:1).
1H NMR (CD3OD): d = 8.06 (d, J = 8.4 Hz, 1 H), 7.44 (d, J = 8.7
Hz, 1 H), 3.23(s, 3 H), 2.70 (s, 3 H).
X-ray Crystal Data
C15H16ClN3O, FW = 289.76, monoclinic, P21/n, a = 7.3072(7) Å,
b = 14.186(1) Å, c = 14.066(2) Å, b = 95.725(2)°, V = 1450.7(3)Å3,
r
calcd = 1.327 Mg/m3, R1 = 0.0556, wR2 = 0.1498, GOF = 1.019.
13C NMR (DMSO-d6): d = 159.212, 151.843, 147.007, 135.627,
3-Isobutyl-2-phenyl-3H-imidazo[4,5-b]quinolin-9-ol (2n)
Yield: 62%; white solid; mp 282–284 °C; Rf = 0.26 (hexane–
EtOAc, 1:1).
131.335, 106.964, 31.057.
MS (EI): m/z = 281 (M+), 269, 253, 240, 213, 124, 91, 71, 57.
1H NMR (CD3OD): d = 7.98 (d, J = 8.1 Hz, 1 H), 7.59 (m, 2 H), 7.49
(m, 2 H), 7.39 (m, 3 H), 2.75 (t, J = 7.2 Hz, 1 H), 3.37 (d, J = 6.6
Hz, 2 H), 2.05 (m, 1 H), 1.12 (s, 3 H), 1.10 (s, 3 H).
13C NMR (CD3OD): d = 199.947, 179.072, 157.235, 144.541,
139.742, 133.946, 131.229, 130.447, 128.918, 128.741, 126.890,
124.858, 124.613, 117.887, 101.945, 30.831, 29.486, 20.578.
HRMS (EI): m/z calcd for C16H9ClN3O: 281.0123; found:
281.0123.
7-(tert-Butyl)-3-(2, 2-diphenylpropyl)-2-methyl-3H-imida-
zo[4,5-b]quinolin-9-ol (2j)
Yield: 48%; white solid; mp 294–295 °C; Rf = 0.11 (hexane–
EtOAc, 1:1).
Synthesis 2008, No. 22, 3569–3578 © Thieme Stuttgart · New York

PAPER
Microwave-Assisted Direct One-Pot Beckmann Rearrangement
3575
MS (EI): m/z = 317 (M+), 302, 274, 263, 249, 199, 114, 77.
1H NMR: d = 7.84 (s, 1 H), 7.78 (d, J = 8.7 Hz, 1 H), 7.62 (d, J = 8.7
Hz, 1 H), 7.37–7.20 (m, 10 H), 5.16 (t, J = 5.7 Hz, 1 H), 4.45 (d,
J = 5.7 Hz, 2 H), 2.65 (s, 3 H), 1.85 (s, 3 H), 1.41 (s, 9 H).
HRMS (EI): m/z calcd for C20H19N3O: 317.1528; found: 317.1516.
2-Methyl-N-propyloxazolo[4,5-c]quinolin-4-amine (3a)
Yield: 11%; waxy solid; Rf = 0.11 (CH2Cl2–MeOH, 30:1).
1H NMR: d = 7.89 (d, J = 8.4 Hz, 1 H), 7.81 (d, J = 8.4 Hz, 1 H),
7.53 (t, J = 7.2 Hz, 1 H), 7.29 (t, J = 7.2 Hz, 1 H), 5.40 (br s, 1 H),
3.68 (q, J = 6.3 Hz, 2 H), 2.71 (s, 3 H), 1.75 (sext, J = 7.2 Hz, 2 H),
1.06 (t, J = 7.2 Hz, 3 H).
13C NMR: d = 147.519, 145.477, 144.325, 128.578, 127.814,
127.264, 126.694, 126.491, 115.484, 50.064, 47.762, 34.903,
31.663, 26.784, 14.656.
MS (EI): m/z = 449 (M+), 268, 252, 238, 181, 165, 106, 77.
HRMS (EI): m/z calcd for C30H31N3O: 449.2467; found: 449.2471.
13C NMR: d = 162.053, 152.082, 150.226, 146.126, 128.608,
126.810, 124.918, 122.213, 119.832, 113.226, 42.674, 23.022,
14.468, 11.598.
6-Chloro-2-ethyl-N-isopropyloxazolo[4,5-c]quinolin-4-amine
(3m)
Yield: 12%; white solid; mp 128–129 °C; Rf = 0.58 (hexane–
EtOAc, 3:1).
MS (EI): m/z = 242 (M+), 227, 212, 199, 184, 142, 114, 102, 93.
1H NMR: d = 7.82 (d, J = 7.8 Hz, 1 H), 7.65 (d, J = 7.8 Hz, 1 H),
7.17 (t, J = 7.8 Hz, 1 H), 5.41 (br d, J = 7.2 Hz, 1 H), 4.70–4.63 (m,
1 H), 3.03 (q, J = 7.8 Hz, 2 H), 1.49 (t, J = 7.8 Hz, 3 H), 1.39 (d,
J = 6.3, 3.0 Hz, 6 H).
13C NMR: d = 167.093, 151.906, 149.439, 142.176, 130.979,
128.810, 125.221, 121.779, 118.752, 114.422, 42.764, 22.812,
22.233, 11.192.
HRMS (EI): m/z calcd for C14H15N3O: 241.1215; found: 241.1214.
N-Isopropyl-2,7,9-trimethyloxazolo[4,5-c]quinolin-4-amine
(3c)
Yield: 8%; white solid; mp 98–99 °C; Rf = 0.31 (hexane–EtOAc,
5:1).
1H NMR: d = 7.47 (s, 1 H), 6.92 (s, 1 H), 5.19 (d, J = 7.8 Hz, 1 H),
4.63–4.56 (m, 1 H), 2.77 (s, 3 H), 2.71 (s, 3 H), 2.44 (s, 3 H), 1.35
(s, 3 H), 1.32 (s, 3 H).
13C NMR: d = 161.748, 149.544, 138.381, 131.617, 125.730,
124.644, 124.384, 111.038, 42.340, 23.408, 21.824, 21.202,
14.730.
MS (EI): m/z = 289 (M+), 274, 259, 247, 232, 219, 164, 102, 84, 50.
HRMS (EI): m/z calcd for C15H16ClN3O: 289.0982; found:
289.0979.
X-ray Crystal Data
C15H16ClN3O, FW = 289.76, monoclinic, P21/c, a = 11.4614(4) Å,
MS (EI): m/z = 269 (M+), 254, 227, 212, 197, 158, 142, 127, 84, 58.
b = 7.9067(3)
V = 1454.27(9) Å3,
wR2 = 0.1508, GOF = 1.063.
Å,
c = 16.7618(5)
Å,
b = 106.785(2)°,
calcd = 1.323 Mg/m3, R1 = 0.0545,
HRMS (EI): m/z calcd for C14H11Cl2N3O: 269.1528; found:
269.1520.
r
N-Allyl-6,9-dichloro-2-methyloxazolo[4,5-c]quinolin-4-amine
(3e)
Yield: 5%; white solid; mp 185–186 °C; Rf = 0.42 (hexane–EtOAc,
3:1).
1H NMR: d = 7.57 (d, J = 8.4 Hz, 1 H), 7.21 (d, J = 8.1 Hz, 1 H),
6.15–6.04 (m, 1 H), 5.73 (br s, 1 H), 5.39 (d, J = 17.1 Hz, 1 H), 5.22
(d, J = 10.2 Hz, 1 H), 4.43 (t, J = 5.1 Hz, 2 H), 2.75 (s, 3 H).
13C NMR: d = 168.623, 150.519, 145.925, 143.362, 135.478,
134.265, 126.684, 122.078, 115.214, 114.897, 54.864, 14.056.
2-Methyl-4-morpholinooxazolo[4,5-c]quinoline (3s)
Yield: 6%; white solid; mp 124–125 °C; Rf = 0.36 (hexane–EtOAc,
3:1).
1H NMR: d = 8.22 (d, J = 8.1 Hz, 1 H), 7.94 (d, J = 8.7 Hz, 1 H),
7.71 (t, J = 7.2 Hz, 1 H), 7.49 (t, J = 7.2 Hz, 1 H), 3.95 (t, J = 4.2
Hz, 4 H), 3.50 (t, J = 4.5 Hz, 4 H), 2.71 (s, 3 H).
13C NMR: d = 168.992, 156.249, 154.218, 146.971, 131.266,
128.005, 125.147, 121.638, 113.906, 108.408, 66.880, 51.187,
12.566.
MS (EI): m/z = 307 (M+), 292, 279, 267, 252, 198, 182, 148, 111,
97, 85, 57.
MS (EI): m/z = 269 (M+), 238, 224, 212, 198, 184, 142, 120, 114,
102, 84, 76.
HRMS (EI): m/z calcd for C14H11Cl2N3O: 307.0279; found:
307.0275.
HRMS (EI): m/z calcd for C15H15N3O2: 269.1164; found: 269.1188.
3-Methyl-N-propylisoxazolo[4,5-c]quinolin-4-amine (4a)
Yield: 8%; white solid; mp 109–110 °C; Rf = 0.43 (CH2Cl2–MeOH,
30:1).
1H NMR: d = 8.09 (d, J = 8.1 Hz, 1 H), 7.79 (d, J = 8.1 Hz, 1 H),
7.62 (t, J = 8.1 Hz, 1 H), 7.31 (t, J = 8.1 Hz, 1 H), 4.87 (br s, 1 H),
3.67 (q, J = 7.2 Hz, 2 H), 2.71 (s, 3 H), 1.77 (sext, J = 7.2 Hz, 2 H),
1.07 (t, J = 7.5 Hz, 3 H).
13C NMR (CD3OD): d = 168.162, 153.305, 151.524, 148.681,
131.086, 126.687, 122.689, 121.490, 112.289, 104.812, 42.863,
22.866, 12.026, 11.574.
8-tert-Butyl-N-cyclobutyl-2-methyloxazolo[4,5-c]quinolin-4-
amine (3f)
Yield: 8%; white solid; mp 127–128 °C; Rf = 0.58 (hexane–EtOAc,
2:1).
1H NMR: d = 8.03 (s, 1 H), 7.74 (d, J = 7.7 Hz, 1 H), 7.60 (d, J = 8.8
Hz, 1 H), 5.53 (d, J = 8.1 Hz, 1 H), 4.89 (quint, J = 8.1 Hz, 1 H),
2.71 (s, 3 H), 2.57–2.48 (m, 2 H), 2.17–1.86 (m, 2 H), 1.83–1.75 (m,
2 H), 1.41 (s, 9 H).
13C NMR: d = 166.072, 150.645, 146.739, 144.176, 134.910,
125.321, 122.779, 121.422, 125.352, 111.776, 54.564, 35.192,
31.506, 30.664, 18.102, 14.004.
MS (EI): m/z = 242 (M+), 227, 213, 200, 183, 169, 144, 114, 84, 76,
58.
MS (EI): m/z = 309 (M+), 294, 280, 266, 240, 224, 155, 119, 84, 57.
HRMS (EI): m/z calcd for C14H15N3O: 241.1215; found: 241.1210.
HRMS (EI): m/z calcd for C19H23N3O: 309.1841; found: 309.1842.
N-Isopropyl-3,7,9-trimethylisoxazolo[4,5-c]quinolin-4-amine
(4c)
Yield: 19%; white solid; mp 134–135 °C; Rf = 0.38 (hexane–
EtOAc, 5:1).
8-tert-Butyl-2-methyl-N-(2,2-diphenylpropyl)oxazolo[4,5-
c]quinolin-4-amine (3j)
Yield: 3%; white solid; mp 87–89 °C; Rf = 0.47 (hexane–EtOAc,
3:1).
Synthesis 2008, No. 22, 3569–3578 © Thieme Stuttgart · New York

3576
B. H. Hwang et al.
PAPER
1H NMR: d = 7.44 (s, 1 H), 6.93 (s, 1 H), 4.63–4.58 (s, m, 1 H), 2.85
MS (EI): m/z = 449 (M+), 268, 252, 224, 181, 103, 77.
(s, 3 H), 2.69 (s, 3 H), 2.44 (s, 3 H), 1.36 (s, 3 H), 1.34 (s, 3 H).
HRMS (EI): m/z calcd for C30H31N3O: 449.2467; found: 449.2473.
13C NMR: d = 169.544, 152.944, 150.963, 150.135, 141.061,
134.164, 126.327, 124.240, 110.377, 104.625, 42.536, 23.345,
22.031, 21.929, 12.205.
6-Chloro-3-ethyl-N-isopropylisoxazolo[4,5-c]quinolin-4-amine
(4m)
Yield: 10%; white solid; mp 108–109 °C; Rf = 0.59 (hexane–
EtOAc, 3:1).
MS (EI): m/z = 269 (M+), 254, 239, 227, 212, 197, 158, 142, 127,
115, 58.
1H NMR: d = 8.01 (d, J = 8.1 Hz, 1 H), 7.74 (d, J = 7.8 Hz, 1 H),
7.21 (t, J = 7.8 Hz, 1 H), 4.78 (br d, J = 6.3 Hz, 1 H), 4.71–4.64 (m,
1 H), 3.06 (q, J = 7.8 Hz, 2 H), 1.51 (t, J = 7.5 Hz, 3 H), 1.39 (dd,
J = 6.5, 3.0 Hz, 6 H).
13C NMR: d = 168.230, 158.349, 150.480, 144.815, 131.142,
130.983, 122.282, 120.260, 113.336, 104.664, 43.112, 22.744,
20.408, 11.845.
HRMS (EI): m/z calcd for C16H19N3O: 269.1528; found: 269.1525.
N-Allyl-6,9-dichloro-3-methylisoxazolo[4,5-c]quinolin-4-amine
(4e)
Yield: 9%; white solid; mp 179–180 °C; Rf = 0.35 (hexane–EtOAc,
3:1).
1H NMR: d = 7.64 (d, J = 8.1 Hz, 1 H), 7.24 (d, J = 8.4 Hz, 1 H),
6.16–6.05 (m, 1 H), 5.38 (d, J = 17.4 Hz, 1 H), 5.26 (d, J = 10.1 Hz,
1 H), 5.17 (br s, 1 H), 4.42 (t, J = 5.1 Hz, 2 H), 2.75 (s, 3 H).
13C NMR: d = 167.73, 152.963, 151.372, 145.827, 134.498,
130.842, 129.986, 127.792, 123.980, 117.535, 113.238, 106.814,
43.966, 12.161.
MS (EI): m/z = 289 (M+), 274, 259, 247, 232, 219, 164, 102, 84, 50.
HRMS (EI): m/z calcd for C15H16ClN3O: 289.0982; found:
289.0986.
X-ray Crystal Data
C15H16ClN3O, FW = 289.76, tetragonal, I41/a, a = 27.6952(2) Å,
MS (EI): m/z = 307 (M+), 292, 280, 272, 253, 182, 148, 86, 56.
b = 27.6952(2)
V = 11698.0(3) Å3,
wR2 = 0.1356, GOF = 1.005.
Å,
c = 15.2512(3)
Å,
a = b = g = 90°,
calcd = 1.316 Mg/m3, R1 = 0.0561,
HRMS (EI): m/z calcd for C14H11Cl2N3O: 307.0279; found:
307.0275.
r
8-tert-Butyl-N-cyclobutyl-3-methylisoxazolo[4,5-c]quinolin-4-
amine (4f)
Yield: 4%; white solid; mp 253–254 °C; Rf = 0.62 (hexane–EtOAc,
2:1).
1H NMR: d = 8.03 (s, 1 H), 7.74–7.67 (m, 2 H), 4.92–4.81 (br s, m,
1 H, 1 H), 2.71 (s, 3 H), 2.59–2.53 (m, 2 H), 1.98–1.82 (m, 2 H, 2
H), 1.41 (s, 9 H).
N-Isobutyl-3-phenylisoxazolo[4,5-c]quinolin-4-amine (4n)
Yield: 22%; white solid; mp 111–112 °C; Rf = 0.70 (hexane–
EtOAc, 3:1).
1H NMR: d = 8.16 (d, J = 8.1 Hz, 1 H), 7.79 (d, J = 8.4 Hz, 1 H),
7.74 (m, 2 H), 7.63 (m, 4 H), 7.33 (t, J = 7.8 Hz, 1 H), 4.90 (br s, 1
H), 3.42 (dd, J = 5.4, 5.4 Hz, 2 H), 1.80 (m, 1 H), 0.89 (s, 3 H), 0.86
(s, 3 H).
13C NMR: d = 166.061, 150.027, 146.723, 144.044, 134.925,
125.361, 122.736, 121.414, 54.505, 35.531, 31.561, 31.532,
30.636, 18.105, 11.629.
13C NMR: d = 168.466, 157.683, 151.304, 148.948, 131.407,
130.798, 129.584, 129.124, 128.670, 126.754, 122.745, 121.673,
112.272, 103.873, 48.421, 28.208, 20.365.
MS (EI): m/z = 309 (M+), 294, 280, 266, 240, 224, 155, 119, 84, 57.
MS (EI): m/z = 317 (M+), 302, 274, 261, 190, 114, 77.
HRMS (EI): m/z calcd for C19H23N3O: 309.1841; found: 309.1843.
HRMS (EI): m/z calcd for C20H19N3O: 317.1528; found: 317.1519.
6,9-Dichloro-N,3-dimethylisoxazolo[4,5-c]quinolin-4-amine (4i)
Yield: 14%; white solid; mp 145–147 °C; Rf = 0.35 (hexane–
EtOAc, 3:1).
3-Methyl-4-morpholinoisoxazolo[4,5-c]quinoline (4s)
Yield 12%; white solid; mp 121–122 °C; Rf = 0.45 (hexane–
EtOAc, 3:1).
1H NMR: d = 7.64 (d, J = 8.1 Hz, 1 H), 7.24 (d, J = 8.4 Hz, 1 H),
6.16–6.05 (m, 1 H), 5.38 (d, J = 17.4 Hz, 1 H), 5.26 (d, J = 10.1 Hz,
1 H), 5.17 (br s, 1 H), 4.42 (t, J = 5.1 Hz, 2 H), 2.75 (s, 3 H).
1H NMR: d = 7.93 (d, J = 7.8 Hz, 1 H), 7.79 (d, J = 8.4 Hz, 1 H),
7.55 (t, J = 8.1 Hz, 1 H), 7.32 (t, J = 7.8 Hz, 1 H), 4.21 (t, J = 4.5
Hz, 4 H), 3.89 (t, J = 4.5 Hz, 4 H), 2.71 (s, 3 H).
13C NMR: d = 167.73, 152.963, 151.372, 145.827, 134.498,
130.842, 129.986, 127.792, 123.980, 117.535, 113.238, 106.814,
43.966, 12.161.
13C NMR: d = 160.702, 153.913, 150.467, 145.328, 128.994,
126.995, 125.670, 122.937, 119.903, 113.254, 67.311, 46.570,
14.528.
MS (EI): m/z = 307 (M+), 292, 280, 272, 253, 182, 148, 86, 56.
MS (EI): m/z = 269 (M+), 238, 224, 212, 198, 184, 142, 130, 114,
102, 84, 76.
HRMS (EI): m/z calcd for C14H11Cl2N3O: 307.0279; found:
307.0275.
HRMS (EI): m/z calcd for C15H15N3O2: 269.1164; found:269.1143.
8-tert-Butyl-3-methyl-N-(2,2-diphenylpropyl)isoxazolo[4,5-
c]quinolin-4-amine (4j)
Yield: 32%; white solid; mp 193–195 °C; Rf = 0.58 (hexane–
EtOAc, 3:1).
1H NMR: d = 8.03 (s, 1 H), 7.78 (d, J = 8.7 Hz, 1 H), 7.71 (d, J = 8.7
Hz, 1 H), 4.48 (d, J = 5.0 Hz, 1 H), 4.42 (d, J = 5.0 Hz, 2 H), 2.13
(s, 3 H), 1.78 (s, 3 H), 1.41 (s, 3 H).
13C NMR: d = 168.359, 153.578, 151.509, 147.159, 146.989,
146.031, 129.762, 128.787, 127.822, 126.836, 126.523, 117.160,
111.988, 105.009, 50.245, 47.718, 34.939, 31.585, 27.620, 11.537.
2-Methyloxazolo[5,4-b]quinolin-9-ol (5o)
Yield: 49%; yellow solid; mp 302–304 °C; Rf = 0.34 (hexane–
EtOAc, 1:1).
1H NMR (CD3OD): d = 8.32 (d, J = 8.1 Hz, 1 H), 7.75 (t, J = 7.7
Hz, 1 H), 7.53 (d, J = 8.1 Hz, 1 H), 7.41 (t, J = 7.5 Hz, 1 H), 2.62 (s,
3 H).
13C NMR (DMSO-d6): d = 173.661, 165.121, 158.227, 138.773,
133.534, 126.108, 124.562, 123.600, 118.730, 100.494, 11.354.
MS (EI): m/z = 200 (M+), 187, 171, 145, 119, 92, 76, 64.
HRMS (EI): m/z calcd for C11H8N2O2: 200.0586; found: 200.0586.
Synthesis 2008, No. 22, 3569–3578 © Thieme Stuttgart · New York

PAPER
Microwave-Assisted Direct One-Pot Beckmann Rearrangement
3577
2,5-Dimethyloxazolo[5,4-b]quinolin-9-ol (5p)
Yield: 48%; yellow solid; mp 297–298 °C; Rf = 0.37 (hexane–
EtOAc, 1:1).
1H NMR (CD3OD): d = 8.19 (d, J = 8.2 Hz, 1 H), 7.60 (d, J = 7.6
Hz, 1 H), 7.30 (t, J = 7.6 Hz, 1 H), 2.62 (s, 3 H), 2.16 (s, 3 H).
13C NMR (DMSO-d6): d = 165.227, 157.617, 134.064, 126.741,
124.378, 123.484, 122.756, 100.024, 17.748, 10.861.
(5) Yoo, K. H.; Choi, E. B.; Lee, H. K.; Yeon, G. H.; Yang, H.
C.; Pak, C. S. Synthesis 2006, 1599.
(6) (a) Mihailovic, M. L.; Rajkovic, M. M.; Lorenc, L. B.;
Pavlovic, V. D.; Milovanovic, A. Z.; Tinant, B.; Declercq,
J.-P. Tetrahedron 1996, 52, 11995. (b) Lee-ruff, E.; Xi, F.;
Qie, J. H. J. Org. Chem. 1996, 61, 1547. (c) Blanco, J. M.;
Caamano, O.; Fernandez, F.; Gomez, G.; Nieto, I. Synthesis
1996, 281. (d) Toshihiko, A.; Toriumi, Y.; Mochizuki, Y.;
Nonomura, T.; Nagaoka, S.; Furukawa, K.; Tsuru, H.;
Adachi-Akahane, S.; Ohwada, T. Bioorg. Med. Chem. 2006,
14, 8014. (e) Tong, S. T.; Barker, D. Tetrahedron Lett. 2006,
47, 5017. (f) Ahn, J. H.; Shin, M. S.; Jung, S. H.; Kang, S.
K.; Kim, K. R.; Rhee, S. D.; Jung, W. H.; Yang, S. D.; Kim,
S. J.; Woo, J. R.; Lee, J. H.; Cheon, H. G.; Kim, S. S. J. Med.
Chem. 2006, 49, 4781. (g) McKinnon, D. M.; Abouzeid, A.
A. J. Heterocycl. Chem. 1991, 28, 749.
MS (EI): m/z = 214 (M+), 185, 172, 159, 133, 105, 89, 77, 63.
HRMS (EI): m/z calcd for C12H10N2O2: 214.0742; found: 214.0735.
2-Phenyloxazolo[5,4-b]quinolin-9-ol (5q)
Yield: 67%; light green solid; mp 211–213 °C; Rf = 0.17 (hexane–
EtOAc, 1:1).
1H NMR (CD3OD): d = 8.36 (d, J = 8.1 Hz, 1 H), 8.31–8.28 (m, 2
H), 7.77 (t, J = 7.6 Hz, 1 H), 7.58–7.51 (m, 4 H), 7.42 (t, J = 7.4 Hz,
1 H).
(7) For the preparation of 2-alkylamino-3-acylquinolinones 1
from 2-alkylthio-3-acylquinolinones, see: Hwang, B. H.;
Park, S. H.; Choi, E. B.; Pak, C. S.; Lee, H. K. Tetrahedron
2008, 64, 6698.
13C NMR (DMSO-d6): d = 161.461, 156.920, 137.442, 131.807,
130.392, 129.895, 129.906, 125.998, 122.587, 120.988, 116.191.
(8) Ren, R. X.; Ou, W. Tetrahedron Lett. 2001, 42, 8445.
(9) (a) Jeong, T. S.; Kim, M. J.; Yu, H.; Kim, K. S.; Choi, J. K.;
Kim, S. S.; Lee, W. S. Bioorg. Med. Chem. Lett. 2005, 15,
1525. (b) Zhao, Y. L.; Chen, Y. L.; Chang, F. S.; Tzeng, C.
C. Eur. J. Med. Chem. 2005, 40, 792. (c) Trofimov, B. A.;
Zaitsev, A. B.; Schmidt, E. Y.; Vasiltov, A. M.; Mikhaleva,
A. I.; Ushakov, I. A.; Vashchenko, A. V.; Zorina, N. V.
Tetrahedron Lett. 2004, 45, 3789.
(10) (a) Shi, H. Synth. Commun. 2006, 36, 237. (b) Trofimov, B.
A.; Zaitsev, A. B.; Schmidt, E. Y.; Vasil’tsov, A. M.;
Mikhaleva, A. L.; Ushakov, I. A.; Vashchenko, A. V.;
Zorina, N. V. Tetrahedron Lett. 2004, 45, 3789.
(11) Diez, A.; Voldoire, A.; Lopez, I.; Rubiralta, M.; Segarra, V.;
Pages, L.; Palacios, J. M. Tetrahedron 1995, 51, 5143.
(12) Linderman, R. J.; Kirollos, K. S. Tetrahedron Lett. 1989, 30,
2049.
(13) Eshghi, H.; Hassankhani, A. Org. Prep. Proced. Int. 2005,
37, 575.
MS (EI): m/z = 262 (M+), 248, 234, 221, 119, 105, 77, 643.
HRMS (EI): m/z calcd for C16H10N2O2: 262.0742; found: 262.0741.
5,8-Dichloro-2-methyloxazolo[5,4-b]quinolin-9-ol (5r)
Yield: 47%; light orange solid; mp 296–297 °C; Rf = 0.13 (hexane–
EtOAc, 1:1).
1H NMR (CD3OD): d = 7.67 (s, 1 H), 7.10 (s, 1 H), 2.64 (s, 3 H).
13C NMR: d = 160.029, 153.587, 150.241, 142.117, 131.329,
127.215, 120.124, 114.131, 104.275, 11.748.
MS (EI): m/z = 268 (M+), 255, 241, 213, 187, 160, 124, 62.
HRMS (EI): m/z calcd for C11H6N2O2: 267.9806; found: 267.9805.
2-Methyloxazolo[5,4-b]quinolin-9-ol (5s)
Yield: 68%; white solid; mp 301–302 °C; Rf = 0.25 (hexane–
EtOAc, 1:1).
1H NMR (CD3OD): d = 8.32 (d, J = 8.4 Hz, 1 H), 7.77 (t, J = 8.1
Hz, 1 H), 7.54 (d, J = 7.8 Hz, 1 H), 7.41 (t, J = 7.8 Hz, 1 H), 3.31 (s,
3 H).
(14) Cvetovich, R. J.; Chung, J. Y. L.; Kress, M. H.; Amato, J. S.;
Matty, L.; Weingarten, M. D.; Tsay, F. R.; Li, Z.; Zhou, G.
J. Org. Chem. 2005, 70, 8560.
(15) (a) Hajipour, B. R.; Mallakpour, S. E.; Imanzadeh, G. J.
Chem. Res., Synop. 1999, 228. (b) Kamakshi, R.; Reddy, B.
S. R. Aust. J. Chem. 2005, 58, 603. (c) Mitra, A. K.; De, A.;
Karchaudhuri, N. J. Indian Chem. Soc. 1999, 76, 218.
(16) Bogdal, D. In Microwave-assisted Organic Synthesis: One
Hundred Reaction Procedures, Tetrahedron Organic
Chemistry Series, Vol. 25; Elsevier: Amsterdam, 2006.
(17) (a) Ghiaci, M.; Bakhtiari, K. Synth. Commun. 2001, 31,
1803. (b) Touaux, B.; Texier-Boullet, F.; Hamelin, J.
Heteroat. Chem. 1998, 9, 351.
(18) (a) Delgado, F.; Cano, A. C.; Garcia, O.; Alvarado, J.;
Velasco, L.; Alvarez, C.; Rudler, H. Synth. Commun. 1992,
22, 2125. (b) Das, B.; Srinivas, K. V. N. S.; Madhusudhan,
P. International Electronic Conferences on Synthetic
Organic Chemistry, November 1-30, 2003; Molecular
Diversity Preservation International: Basel, 2003, 1078.
(c) Das, B.; Madhusudhan, P.; Venkataiah, B. Synlett 1999,
1596. (d) Das, B.; Ravindranath, N.; Venkataiah, B.;
Madhusudhan, P. J. Chem. Res., Synop. 2000, 482.
(e) Srinivas, K. V. N. S.; Reddy, E. B.; Das, B. Synlett 2002,
625. (f) Firouzabadi, H.; Iranpoor, N.; Karimi, B.;
Hazarkhani, H. Synlett 2000, 263. (g) Gopalakrishnan, M.;
Sureshkumar, P.; Kanagarajan, V.; Thanusu, J. Lett. Org.
Chem. 2005, 2, 444. (h) Eshghi, H.; Gordi, Z. Synth.
Commun. 2003, 33, 2971.
13C NMR (CD3OD): d = 173.661, 165.121, 158.227, 138.773,
133.534, 126.108, 124.562, 123.600, 118.730, 100.495, 11.354.
MS (EI): m/z = 200 (M+), 171, 145, 130, 119, 103, 92, 76, 52.
HRMS (EI): m/z calcd for C11H8N2O2: 200.0586; found: 200.0584.
Acknowledgment
This research was supported by grants from the Ministry of Science
and Technology of Korea and the Center for Biological Modulators
of the 21st Century Frontier R & D Program, the Ministry of
Science and Technology of Korea (CBM31-A1200-00-00-00).
References
(1) Drug Data Rep. 2004, 26, 1059.
(2) Drug Data Rep. 2000, 22, 455.
(3) Boer, R.; Ulrich, W.-R.; Martin, T.; Graedler, U. PCT WO
076451 A1, 2004; Chem. Abstr. 2004, 141, 260751.
(4) Gerster, J. F.; Lindstrom, K. J.; Marszalek, G. J.; Merrill, B.
A.; Mickelson, J. W.; Rice, M. J. PCT Int. Appl. WO
2000006577, 2000; Chem. Abstr. 2000, 132, 137381.
Synthesis 2008, No. 22, 3569–3578 © Thieme Stuttgart · New York

3578
B. H. Hwang et al.
PAPER
(19) (a) Loupy, A.; Regnier, S. Tetrahedron Lett. 1999, 40, 6221.
(b) Bhawal, B. M.; Mayabhate, S. P.; Likhite, A. P.;
Deshmukh, A. R. A. S. Synth. Commun. 1995, 25, 3315.
(c) Fujita, S.; Koyama, K.; Inagaki, Y. Synthesis 1982, 68.
(d) Yamamoto, K.; Watanabe, H. Chem. Lett. 1982, 1225.
(20) (a) Heuser, S.; Keenan, M.; Weichert, A. G. Tetrahedron
Lett. 2005, 46, 9001. (b) Yoshinobu, T.; Yoshinobu, G.
Heterocycles 1987, 26, 2921.
(21) (a) Sun, L.-Q.; Chen, J.; Takaki, K.; Johnson, G.; Iben, L.;
Mahle, C. D.; Ryan, E.; XU, C. Bioorg. Med. Chem. Lett.
2004, 14, 1197. (b) Stokker, G. J. Org. Chem. 1983, 48,
2613.
(22) Yang, Y.-H.; Shi, M. Tetrahedron 2006, 62, 2420.
(23) (a) Dubey, P. K.; Kumar, R. V. Indian J. Chem., Sect B: Org.
Chem. Incl. Med. Chem. 2000, 39, 746. (b) Katagiri, N.;
Koshihara, A.; Atsume, S.; Kato, T. J. Org. Chem. 1982, 47,
167.
(24) Kempter, F. E.; Rokos, H.; Pfleiderer, W. Chem. Ber. 1970,
103, 885.
(25) X-ray crystal structure analysis of 2m, 3m, and 4m: atomic
coordinates, bond lengths [Å] and angles [°], anisotropic
displacement parameters, hydrogen coordinates, torsion
angles [°] have been deposited at Cambridge
Crystallographic Data Centre 12, Union Road, Cambridge
CB2 1EZ, UK under deposition number CCDC 645836 for
2m, CCDC 646585 for 3m, and CCDC 647425 for 4m [fax:
+44(1223)336 033, E-mail:deposit@ccdc.cam.ac.uk].
(26) Bruker SMART Version 5.6 Data Collection Software and
SAINT Version 7.12A Data Processing Software for the
SMART APEX II System; Bruker AXS Inc.: Madison WI /
USA, 2005.
(27) Sheldrick, G. M. SHELXTL DOS/Windows/NT Version 6.14;
Bruker AXS Inc.: Madison WI / USA, 2005.
Synthesis 2008, No. 22, 3569–3578 © Thieme Stuttgart · New York