Synthesis of 2-heptyl-1-hydroxy-4(1H)-quinolone - Unexpected rearrangement of 4-(alkoxycarbonyloxy)quinoline N-oxides to 1-(alkoxycarbonyloxy)-4(1H)- quinolones

Article abstract of DOI:10.1055/s-2007-966020

2-Heptyl-4(1H)-quinolone was converted in two steps into the 4-ethoxycarbonyloxy-, 4-(tert-butoxycarbonyloxy)-, and 4- (dimethylaminocarbonyloxy)quinoline N-oxides. While the former two rearranged to the corresponding 1-(alkoxycarbonyloxy)-4(1H)-quinolones at room temperature, the latter was stable, even at 140°C in refluxing xylenes. Basic hydrolysis of these compounds furnished 2-heptyl-1-hydroxy-4(1H)-quinolone. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-966020

PAPER
1517
Synthesis of 2-Heptyl-1-hydroxy-4(1H)-quinolone – Unexpected Rearrange-
ment of 4-(Alkoxycarbonyloxy)quinoline N-Oxides to 1-(Alkoxycarbonyloxy)-
4(1H)-quinolones
R
earrangement of
n
4-(Alkoxyc
a
n
rbonyloxy)qu
a
inoline
N
-Oxide
W
to 4(1
H
)-Quinolones oschek,a Marek Mahout,a Kurt Mereiter,b Friedrich Hammerschmidt*a
a
Institut für Organische Chemie, Universität Wien, Währingerstraße 38, 1090 Vienna, Austria
Fax +43(1)427795231; E-mail: friedrich.hammerschmidt@univie.ac.at
Institute of Chemical Technologies and Analytics, Vienna University of Technology, Getreidemarkt 9/164SC, 1060 Vienna, Austria
b
Received 22 December 2006; revised 28 February 2007
O
Abstract: 2-Heptyl-4(1H)-quinolone was converted in two steps
into the 4-ethoxycarbonyloxy-, 4-(tert-butoxycarbonyloxy)-, and 4-
(dimethylaminocarbonyloxy)quinoline N-oxides. While the former
two rearranged to the corresponding 1-(alkoxycarbonyloxy)-4(1H)-
quinolones at room temperature, the latter was stable, even at
140 °C in refluxing xylenes. Basic hydrolysis of these compounds
furnished 2-heptyl-1-hydroxy-4(1H)-quinolone.
1a
b
R = n-C7H15 (HQNO)
R = n-C9H19
c
N
R
R = n-C11H23
OH
O
Key words: acylations, heterocycles, quinolines, rearrangements,
oxidations
N
OH
Aurachin C (2)
Lightbown isolated from culture filtrates of Pseudomonas
aeruginosa a product, which antagonized the antibacterial
action of streptomycin and dihydrostreptomycin.1,2 Corn-
forth and James proved the product to be a mixture and
synthesized its principal constituents 1a–c (Figure 1).3
The major component was 1a, the n-heptyl derivative of
1-hydroxy-4(1H)-quinolone [acronym: HQNO = 2-hep-
tyl-4-hydroxyquinolone N-oxide, IUPAC: 2-heptyl-1-hy-
droxy-4(1H)-quinolone], and the most active one was
found to be 1b, the n-nonyl derivative. In the same year
Lightbown and Jackson disclosed their finding that
HQNO inhibits the cytochrome system of heart muscle
and Staphylococcus aureus.4 HQNO and other 4-hydroxy-
quinoline N-oxides and the underlying quinolones are in-
hibitors of respiratory5,6 and photosynthetic electron7
transport chains. Furthermore, HQNO was found to selec-
tively block one (quinol oxidase) of the three respiratory
terminal oxidases in the cyanobacterium Synechocystis
sp. strain PCC6803.8 Aurachin C9 (2, Figure 1), isolated
from the biomass of Stigmatella aurantiaca, shows a
close chemical and inhibitory relationship10 to HQNO.
Figure 1 Naturally occurring 1-hydroxy-4(1H)-quinolones 1 and 2
oxide 5 was hydrolyzed to yield HQNO (1a) (Scheme 1).
Ames et al. transformed 3 into benzyl ether 6, oxidized
(MCPBA) it and deblocked (Pd/SrCO3/H2) the protected
N-oxide 7 to get 1a.12 The former method was used later
by others to prepare a variety of analogues with other n-
alkyl groups in place of the heptyl group.5
Needing for biological experiments HQNO, which was no
longer commercially available, we decided to synthesize
it. The method starting with the acylation of the 4-(1H)-
quinolone seemed to be more attractive than any other
O
O
O
N
OEt
R
1) NaOH
2) EtOC(O)Cl
MCPBA
N
R
H
O
3
4
R = n-C7H15
O
The first syntheses of 1-hydroxy-4(1H)-quinolones 1
were performed by Cornforth and James.3 They started
from o-nitrobenzoyl chloride and the respective methyl 3-
oxoalkanoate, which were condensed. The acylated ester
was hydrolyzed and decarboxylated to give the 1,3-dike-
tone. Its nitro group was reduced with SnCl2·2H2O and the
nitroso compound cyclized to the desired compound. Al-
ternatively for HQNO, they acylated 4(1H)-quinolone11 3
and oxidized it at nitrogen using MCPBA. The crude N-
OEt
R
1) POCl3
2) KOH, BnOH
N
O
5
Bn
1) KOH
2) H+
Bn
O
O
Pd, SrCO3, H2
MCPBA
1a
N
O
R
N
R
SYNTHESIS 2007, No. 10, pp 1517–1522
Advanced online publication: 18.04.2007
x
x.
x
x
.
2
0
0
7
6
7
Scheme 1
DOI: 10.1055/s-2007-966020; Art ID: T18306SS
© Georg Thieme Verlag Stuttgart · New York

1518
A. Woschek et al.
PAPER
method. We were surprised to find that N-oxide 5 isomer- tentatively assigned to the crystalline isomer (Scheme 3).
ized easily. This unknown rearrangement forms the basis It is an O-acylated vinylogous hydroxamic acid ester and
of this work. Additionally, we optimized the inadequately slightly less polar than N-oxide 5. This structure was se-
described steps with in part missing yields and character- cured by a single crystal X-ray structure analysis
ized the products spectroscopically, which has not been (Figure 2). With spectroscopic data of 12 in hands, we
done previously.
were able to detect trace amounts of it already in oily 5.
This rearrangement proceeds quantitatively and very
smoothly in neat samples already at room temperature (3
days for 5). When an NMR sample was kept at room tem-
At first, we prepared 4(1H)-quinolone 3 by condensing
aniline with ethyl 3-oxodecanoate using a catalytic
amount of p-toluenesulfonic acid in hexanes and azeotro-
pic removal of the water according to a literature
procedure13 (Scheme 2). Then, the crude enamine was cy-
clized in refluxing diphenyl ether (bp 259 °C) to give
crystalline 4(1H)-quinolone 3 in 52% yield. Treatment of
3 with t-BuOK in anhydrous THF furnished the potassium
salt which was esterified without prior isolation as in the
case of the sodium salt with ethyl chloroformate to give 4-
(ethoxycarbonyloxy)quinoline 4 in 85% yield. Oxidation
with MCPBA furnished N-oxide 5 as a viscous oil (92%)
resisting crystallization.
1
perature and a H NMR spectrum was recorded at inter-
vals of two days, the isomerization seemed to be
extremely slow. To study the effect of replacing R2 = Et
by R2 = t-Bu, N-oxide 11 was prepared similarly to 5
(Scheme 2). The potassium salt of quinolone 3 was acylat-
ed with Boc2O to give 10 in 92% yield. Oxidation with
MCPBA produced 11 (74%) as a viscous oil, which rear-
ranged more slowly than 5. Its chemical and physical
properties and spectroscopic data are similar to those of 5.
A neat sample, when left at room temperature for 16 days,
was a mixture of N-oxide 11 (20%), its isomer 13 (60%)
and HQNO formed by hydrolysis of 13.
O
O
1) p-TsOH⋅H2O,
To the best of our knowledge, this rearrangement has not
yet been described in the literature, although 2-alkyl-1-
hydroxy-4(1H)-quinolones have been prepared via the
corresponding 4-(ethoxycabonyloxy)quinoline N-ox-
ides.3,7,14 Usually, the N-oxides were not isolated and
hexanes
CO2Et
+
R1
2) Ph2O, reflux
N
R1
NH2
O
H
8
9
52%
3
O
R1 = n-C7H15
OR2
OR2
R1
O
O
O
MCPBA,
CH2Cl2
O
1) t-BuOK, THF
OR2
R1
O
N
2) EtOC(O)Cl
or Boc2O
R1
N
O
r.t.
N
N
O
R1
OR2
20 °C
4 R2 = Et, 85%
10 R2 = t-Bu, 92%
5 R2 = Et, 92%
11 R2 = t-Bu, 74%
O
5 R1 = C7H15, R2 = Et
11 R1 = C7H15, R2 = t-Bu
12 R1 = C7H15, R2 = Et
13 R1 = C7H15, R2 = t-Bu
Scheme 2
Scheme 3
Once, when a neat sample of N-oxide 5 was left for three
days at room temperature, it had solidified. Surprisingly,
the 1H NMR spectrum of this material was completely dif-
ferent from that of the oil. The same was true for its 13C
NMR and the IR spectra. The product was crystallized
from diisopropyl ether (30 to 4 °C) to yield colorless crys-
tals with a low melting point (64–65 °C). As the microan-
alytical data of the crystals and the oil agreed within
experimental error, the two compounds had to be isomers.
The oil showed in the IR spectrum one characteristic ab-
sorption at 1769 cm–1 (OCO2Et), similar to the one in 4
(1770 cm–1), but different from that of the crystalline
product having three (1803, 1634 and 1604 cm–1). The 1H
NMR spectrum of the oily product revealed a significant
singlet at 7.32 ppm (7.29 ppm in 4), but shifted to 6.09
ppm in the crystalline product. Finally, the 13C NMR spec-
trum of the crystalline product showed a significant reso-
nance at 177.3 ppm, which was not present in the other
compounds, but characteristic for a C=O [in addition to
the C=O of the OC(O)OEt at 153.1 ppm]. The 13C NMR
spectrum of the oil has the lowest resonance at 152.4 ppm.
On the basis of these spectroscopic data, structure 12 was
Figure 2 Molecular structure of quinolone 12 in the solid state.
Only the first one of the four independent molecules is shown. Selec-
ted bond lengths (Å): N1–O2 1.398(1), N1–C1 1.365(2), N1–C9
1.380(2), C1–C2 1.360(2), C9–C4 1.405(2), C2–C3 1.439(2), C4–C3
1.476(2), C3–O1 1.241(2).
Synthesis 2007, No. 10, 1517–1522 © Thieme Stuttgart · New York

PAPER
Rearrangement of 4-(Alkoxycarbonyloxy)quinoline N-Oxides to 4(1H)-quinolones
1519
characterized, but immediately deprotected. The mecha- sis of the spectroscopic data (1H and 13C NMR) recorded
nism of the rearrangement is unclear. We favor an inter- in MeOH-d4, 1a is a quinolone and not the tautomeric 4-
molecular transfer of the alkoxycarbonyl group from the hydroxyquinoline N-oxide (see unpublished results in ref.
oxygen at C-4 to that at N via possible intermediates 14 10).
and 15, respectively, and 16 (Scheme 4). It is noteworthy
that the energy gain of the rearrangement outweighs the
dearomatization of the heterocyclic ring. If the proposed
In summary, we have shown that 4-alkoxycarbonyloxy-2-
heptylquinoline N-oxides isomerize by a novel rearrange-
ment to N-alkoxycarbonyloxy-2-heptyl-4(1H)-quinolo-
mechanism applies, it should be a general reaction of 4-
nes at room temperature. The 4-dimethylamino-
alkoxycarbonyloxy-, possibly also of 4-acyloxy-, but not
carbonyloxy analogue is stable even in refluxing xylenes.
of (dialkylaminocarbonyloxy)pyridine N-oxides, de-
scribed in a patent15 for the preparation of insecticidal
1H NMR and 13C NMR (J modulated) spectra were measured in
CDCl3 or MeOH-d4 at 300 K on a Bruker Avance DRX 400 spec-
trometer at 400.13 and 100.61 MHz, respectively. Chemical shifts
compounds. To prove that, the 4-(dimethylaminocarbon-
yloxy)quinoline 17 was prepared similarly to the carbon-
ates 4 and 10 in 92% yield (Scheme 5). Oxidation of 17
were referenced to residual CHCl3 (dH = 7.24) or MeOH-d4
with MCPBA proceeded more rapidly than with 4 or 10 to
give crystalline N-oxide 18. It could not be induced to re-
arrange to the isomeric N-(dimethylaminocarbonyloxy)-
4(1H)-quinolone, neither by refluxing for three hours in
acetonitrile nor in xylenes.
(dH = 3.31) and CDCl3 (dC = 77.00) or MeOH-d4 (dC = 49.00). IR
spectra were run on a PerkinElmer 1600 FT-IR spectrometer; sam-
ples were measured as films [normally, a solution in CDCl3 (from
the NMR sample) was applied and the solvent was allowed to evap-
orate] on a silicon disc;16 the IR of HQNO was recorded with a dia-
mond ATR equipment. TLC was carried on 0.25 mm thick Merck
plates, silica gel 60 F254. Flash chromatography was performed with
Merck silica gel 60 (230–400 mesh). Spots were visualized by UV
and/or I2 or dipping the plate into a solution of (NH4)6Mo7O24·4H2O
(23.0 g) and of Ce(SO4)2·4H2O (1.0 g) in 10% aq H2SO4 (500 mL),
followed by heating with a hot gun. Melting points were determined
on a Reichert Thermovar instrument and were uncorrected.
O
O
OR2
R1
O
O
OR2
O
2
+
N
O
R1
OR2
N
O
N
O
R1
X-ray crystal structure data of 12 were measured on a Bruker Smart
CCD area detector diffractometer using graphite-monochromated
MoKa radiation (l = 0.71073 Å) and 0.3° w-scan frames covering
a complete sphere of the reciprocal space.17 The structure was
solved by direct methods and refined on F2 with the program system
SHELX97.18 All non-hydrogen atoms were refined anisotropically.
Hydrogen atoms were inserted in idealized positions and were re-
fined riding with the atoms to which they were bonded.
5, 11
16
O
14, 15
R1 = n-C7H15
5, 12, 14: R2 = Et
11, 13, 15: R2 = t-Bu
2 x 12 or 13
Scheme 4
2-Heptyl-4(1H)-quinolone (3)
A solution of ethyl 3-oxodecanoate (5.06 g, 23.6 mmol, prepared
according to literature19 or by alkylation of the dianion derived from
ethyl acetoacetate with n-C6H13I in analogy to the procedure for the
preparation of ethyl 3-oxononanoate20), aniline (2.20 g, 2.15 mL,
23.6 mmol), and PTSA (0.070 g, 0.37 mmol) in hexanes (24 mL)
was heated at reflux using a Dean–Stark water separator for 5 h.13
The solution was concentrated under reduced pressure and the resi-
due was added dropwise to refluxing diphenyl ether (5.9 mL). Re-
fluxing was continued for 30 min and the formed EtOH was
removed by distillation. After cooling, Et2O (15 mL) and 2 M HCl
(20 mL) were added and the mixture was left for 18 h at r.t. If a crys-
talline solid had formed, it was collected and washed with Et2O. If
no solid formed, ammonia was added to basify the mixture and then
a solid formed. The crude product was crystallized from EtOAc by
slowly cooling to 4 °C. A second crop was obtained by concentrat-
ing the mother liquor; combined yield of 4(1H)-quinolone 3: 2.965
g (52%); mp 145 °C (Lit.11 mp 146–147 °C).
O
O
Me2N
O
N
Me2N
O
MCPBA,
CH2Cl2
1) t-BuOK, THF
3
2) Me2NC(O)Cl
90%
R1
N
O
R1
92%
R1 = n-C7H15
17
18
Scheme 5
Finally, the N-oxides 5, 11 and 18 and N-(ethoxycarbonyl-
oxy)-4(1H)-quinolone 12 were hydrolyzed smoothly by
potassium hydroxide in aqueous ethanol in one hour.
Acidification and crystallization gave HQNO (1a) in
yields of 71–85% (Scheme 6). The sequence via 3, 4, and
5 represents an optimized synthesis of HQNO. On the ba-
IR (Si): 2927, 1635, 1594, 1552, 1509, 1472 cm–1.
1H NMR (CDCl3): d = 13.39 (br s, 1 H, NH), 8.36 (dd, J = 8.3, 1.3
Hz, 1 Harom), 8.08 (d, J = 8.3 Hz, 1 Harom), 7.62 (ddd, J = 8.3, 7.1, 1.3
Hz, 1 Harom), 7.39 (dd, J = 8.3, 7.1 Hz, 1 Harom), 6.48 (s, 1 H, =CH),
2.84 (t, J = 7.8 Hz, 2 H, CH2), 1.74 (quint, J = 7.8 Hz, 2 H, CH2),
1.27 (m, 2 H, CH2), 1.15 (m, 6 H, CH2), 0.77 (t, J = 7.0 Hz, 3 H,
CH3).
O
1) KOH, EtOH, H2O
5,11,18,12
2) H+/H2O
N
C7H15
71–85%
OH
1H NMR (MeOH-d4): d = 8.20 (dd, J = 8.1 Hz, 1 Harom), 7.65 (t,
J = 8.1 Hz, 1 Harom), 7.56 (d, J = 8.1 Hz, 1 Harom), 7.36 (t, J = 8.1 Hz,
1 Harom), 6.21 (s, 1 H, =CH), 2.68 (t, J = 7.7 Hz, 2 H, CH2), 1.73
1a
Scheme 6
Synthesis 2007, No. 10, 1517–1522 © Thieme Stuttgart · New York

1520
A. Woschek et al.
PAPER
(quint, J = 7.7 Hz, 2 H, CH2), 1.33 (m, 8 H, CH2), 0.87 (t, J = 6.7
Hz, 3 H, CH3).
13C NMR (MeOH-d4): d = 180.6, 157.1, 141.6, 133.3, 126.0, 125.5,
125.0, 119.1, 108.8, 35.0, 32.8, 30.2, 30.1, 30.0, 23.6, 14.4.
13C NMR (CDCl3): d = 177.3, 153.1, 152.1, 139.2, 132.7, 126.7,
125.0, 124.1, 112.2, 108.5, 67.8, 31.6, 30.7, 29.0, 28.8, 27.3, 22.5,
14.1, 14.0.
Anal. Calcd for C19H25NO3: C, 68.86; H, 7.60; N, 4.23. Found: C,
68.91; H, 7.41; N, 4.28.
4-Ethoxycarbonyloxy-2-heptylquinoline (4)
A mixture of t-BuOK (0.701 g, 6.25 mmol, 1.25 equiv) and 4(1H)-
quinolone 3 (1.217 g, 5 mmol) in anhyd THF (36 mL) was stirred
for 1 h at r.t. Ethyl chloroformate (0.597 g, 0.53 mL, 5.5 mmol) was
added and stirring was continued for 30 min. The reaction was
quenched with H2O (10 mL) and the mixture was concentrated un-
der reduced pressure after 5 min. H2O (10 mL) was added to the res-
idue and the product was extracted with EtOAc (3 × 20 mL). The
combined organic layers were dried (Na2SO4) and concentrated un-
der reduced pressure to leave a residue, which was purified by flash
chromatography (EtOAc, Rf = 0.92, starting material: Rf = 0.25) to
give carbonate 4 (1.334 g, 85%) as an oil.
X-ray Crystal Data of 4(1H)-quinolone 1221
Salient crystallographic data are: C19H25NO4, M = 331.40, T = 100
K, triclinic, space group P–1 (no. 2), a = 8.9481(5),
b = 17.9486(10), c = 22.3840(12) Å, a = 85.109(1)°, b =
84.633(1)°, g = 80.510(1)°, V = 3521.3(3) Å3, Z = 8, Dc =
1.250 g cm–3, m(Mo-Ka) = 0.087 mm–1, 64928 reflections collected
of which 20393 were independent and 14902 observed [I > 2s(I)].
R1 = 0.0564, wR2 = 0.1424 [for I > 2s(I)]. The structure at T = 100
K was remarkable in that it contained four independent molecules
which differ pairwise in the conformation of the heptyl chain (two
molecules with anti-coplanar chains, two molecules with synclinal
configurations for C(12)–C(13)–C(14)–C(15) (see Figure 2). At
T = 173 K and above the structure is monoclinic, space group C2/c,
a = 13.8037(7), b = 11.5567(6), c = 22.6319(11) Å, b = 97.729(1)°,
V = 3577.6(3) Å3, Z = 8, and has disordered heptyl chains.
IR (Si): 2928, 2856, 1770, 1239 cm–1.
1H NMR (CDCl3): d = 8.04 (dd, J = 8.6, 1.0 Hz, 1 Harom), 7.97 (dd,
J = 8.3, 1.5 Hz, 1 Harom), 7.69 (ddd, J = 8.6, 7.1, 1.5 Hz, 1 Harom),
7.49 (ddd, J = 8.3, 7.1, 1.0 Hz, 1 Harom), 7.29 (s, 1 H, =CH), 4.38 (q,
J = 7.1 Hz, 2 H, OCH2), 2.95 (~t, J = 8.0 Hz, 2 H, CH2), 1.80 (m, 2
H, CH2), 1.42 (t, J = 7.1 Hz, 3 H, CH3), 1.44–1.21 (m, 8 H, CH2),
0.86 (t, J = 7.0 Hz, 3 H, CH3).
13C NMR (CDCl3): d = 164.1, 154.3, 152.4, 149.6, 130.0, 128.9,
126.0, 120.9, 120.4, 111.8, 65.4, 39.6, 31.7, 29.8, 29.5, 29.1, 22.6,
14.2, 14.0.
4-(tert-Butoxycarbonyloxy)-2-heptylquinoline (10)
4(1H)-Quinolone 3 (0.487 g, 2 mmol) was converted into carbonate
10 in analogy to the preparation of carbonate 4, using Boc2O (0.480
g, 2.2 mmol) in anhyd THF (2 mL) and heating the mixture at 60 °C
for 1 h. The crude product was purified by flash chromatography
(hexanes–EtOAc, 7:1, Rf = 0.45) to yield carbonate 10 (0.635 g,
92%) as an oil.
IR (Si): 2929, 1766, 1605, 1247, 1145 cm–1.
4-Ethoxycarbonyloxy-2-heptylquinoline N-Oxide (5) and
N-Ethoxycarbonyloxy-2-heptyl-4(1H)-quinolone (12)
1H NMR (CDCl3): d = 8.03 (dd, J = 8.3, 1.3 Hz, 1 Harom), 7.96 (dd,
J = 8.3, 1.5 Hz, 1 Harom), 7.67 (ddd, J = 8.3, 7.1, 1.5 Hz, 1 Harom),
7.47 (ddd, J = 8.3, 7.1, 1.3 Hz, 1 Harom), 7.25 (s, 1 H, =CH), 2.94 (t,
J = 7.9 Hz, 2 H, CH2), 1.79 (m, 2 H, CH2), 1.58 (s, 9 H, t-C4H9),
1.43–1.20 (m, 8 H, CH2), 0.85 (t, J = 6.9 Hz, 3 H, CH3).
13C NMR (CDCl3): d = 164.0, 154.3, 150.5, 149.5, 129.8, 128.8,
125.9, 121.0, 120.7, 112.0, 84.4, 39.6, 31.7, 29.8, 29.5, 29.1, 27.6,
22.6, 14.0.
A solution of quinoline 4 (0.995 g, 3.15 mmol) and MCPBA (0.760
g, 77%, 3.39 mmol) in anhyd CH2Cl2 (15 mL) was stirred for 3 h at
r.t. (TLC: EtOAc). The solution was washed with aq 0.5 M Na2CO3
(2 × 5 mL) and H2O (5 mL), dried (Na2SO4), and concentrated under
reduced pressure. The residue was purified by flash chromatogra-
phy (EtOAc, Rf = 0.68) to give N-oxide 5 (0.964 g, 92%) as an oil.
When the oil was left at room temperature for 3 days, a crystalline
1
solid had formed and no N-oxide could be detected by H NMR
spectroscopy. Crystallization from i-Pr2O (30 → 4 °C) furnished
colorless crystals (mp 64–65 °C) of the N-substituted 4(1H)-qui-
nolone 12.
Anal. Calcd for C21H29NO3: C, 73.44; H, 8.51; N, 4.08. Found: C,
73.45; H, 8.66; N, 3.96.
4-(tert-Butoxycarbonyloxy)-2-heptylquinoline N-Oxide (11)
and N-(tert-Butoxycarbonyloxy)-2-heptyl-4(1H)-quinolone (13)
4(1H)-Quinoline 10 (0.503 g, 1.46 mmol) was converted into N-ox-
ide 11 in analogy to the preparation of N-oxide 5, except that the
mixture was stirred under argon for 4 h at 0 °C (TLC: EtOAc). The
crude product was purified by flash chromatography (hexanes–
EtOAc, 2:1, Rf = 0.25) to give N-oxide 11 (0.387 g, 74%) as a vis-
cous oil. When the NMR sample was left at r.t., 0.6%, 1.1% and 3%
had rearranged after 9, 16 and 29 days, respectively. When a sample
of oily N-oxide was left at r.t. for 18 days, the rearrangement was
virtually finished. i-Pr2O (4 mL) was added to the mixture. Filtra-
tion gave a solution, which left an oil on concentration. Two crys-
tallization from i-Pr2O–hexanes (slow cooling from 20 to –27 °C)
furnished an analytical sample of the rearranged product 13; mp 70–
72 °C.
5
IR (Si): 2929, 1769, 1239 cm–1.
1H NMR (CDCl3): d = 8.77 (dd, J = 8.5, 0.9 Hz, 1 Harom), 7.97 (dd,
J = 8.1, 1.1 Hz, 1 Harom), 7.76 (ddd, J = 8.5, 7.0, 1.1 Hz, 1 Harom),
7.60 (ddd, J = 8.1, 7.0, 0.9 Hz, 1 Harom), 7.32 (s, 1 H, =CH), 4.38 (q,
J = 7.1 Hz, 2 H, OCH2), 3.10 (t, J = 7.8 Hz, 2 H, CH2), 1.79 (quint,
J = 7.5 Hz, 2 H, CH2), 1.43 (t, J = 7.1 Hz, 3 H, CH3), 1.43 (m, 2 H,
CH2), 1.35 (m, 2 H, CH2), 1.26 (m, 4 H, CH2), 0.85 (t, J = 7.1 Hz, 3
H, CH3).
13C NMR (CDCl3): d = 152.4, 149.5, 143.6, 142.3, 130.9, 128.0,
122.6, 121.8, 120.1, 113.2, 65.7, 31.7, 29.5, 29.0, 26.0, 22.6, 14.1,
14.0.
12
IR (Si): 2930, 2857, 1803, 1634, 1604, 1487, 1466, 1230 cm–1.
11
1H NMR (CDCl3): d = 8.33 (dd, J = 8.2, 1.4 Hz, 1 Harom), 7.62 (ddd,
J = 8.5, 7.1, 1.4 Hz, 1 Harom), 7.34 (ddd, J = 8.2, 7.1, 1.0 Hz, 1
Harom), 7.27 (dd, J = 8.5, 1.0 Hz, 1 Harom), 6.09 (s, 1 Harom), 4.44 (q,
J = 7.1 Hz, 2 H, OCH2), 2.55 (m, 2 H, CH2), 1.68 (m, 2 H, CH2),
1.42 (t, J = 7.1 Hz, 3 H, CH3), 1.43–1.20 (m, 8 H, CH2), 0.86 (t,
J = 6.8 Hz, 3 H, CH3).
IR (Si): 2928, 1766, 1371, 1248, 1143, 1112 cm–1.
1H NMR (CDCl3): d = 8.77 (dd, J = 8.5, 1.0 Hz, 1 Harom), 7.97 (dd,
J = 8.2, 1.3 Hz, 1 Harom), 7.76 (ddd, J = 8.5, 7.0, 1.3 Hz, 1 Harom),
7.61 (ddd, J = 8.2, 7.0, 1.0 Hz, 1 Harom), 7.29 (s, 1 H, =CH), 3.10 (t,
J = 7.8 Hz, 2 H, CH2), 1.80 (quint, J = 7.8 Hz, 2 H, CH2), 1.58 (s, 9
H, t-C4H9), 1.44 (m, 2 H, CH2), 1.36 (m, 2 H, CH2), 1.28 (m, 4 H,
CH2), 0.86 (t, J = 7.0 Hz, 3 H, CH3).
Synthesis 2007, No. 10, 1517–1522 © Thieme Stuttgart · New York

PAPER
Rearrangement of 4-(Alkoxycarbonyloxy)quinoline N-Oxides to 4(1H)-quinolones
1521
13C NMR (CDCl3): d = 150.4, 149.6, 143.8, 142.3, 130.7, 127.9,
122.8, 121.9, 120.1, 113.4, 85.0, 31.71, 31.68, 29.5, 29.0, 27.6,
26.0, 22.6, 14.0.
2-Heptyl-1-hydroxy-4(1H)-quinolone (1a); Deblocking of Pro-
tected 4(1H)-Quinoline-N-oxides 5, 11, 18, and N-(Ethoxycar-
bonyloxy)-2-heptyl-4(1H)-quinolone (12); General Procedure
Aq 5 M KOH (2.5 mL) was added to a solution of the respective
substrate (1 mmol) in EtOH (5 mL). After 1 h at r.t., H2O (15 mL)
was added and the pH was brought to 1–2 using concd HCl, where-
upon a milky suspension formed which soon crystallized. The prod-
uct was collected by suction, washed with H2O and crystallized
(EtOH–H2O, 4:1) to yield 1a as colorless leaflets; mp 158–159 °C
(Lit.3 mp 158–160 °C; Lit.12 mp 153–155 °C).
Anal. Calcd for C21H29NO4: C, 70.17; H, 8.13; N, 3.90. Found: C,
70.39; H, 8.16; N, 3.84.
13
IR (Si): 2931, 1799, 1634, 1604, 1488, 1466, 1244, 1152, 1139,
1110 cm–1.
1H NMR (CDCl3): d = 8.34 (dd, J = 8.1, 1.3 Hz, 1 Harom), 7.62 (ddd,
J = 8.1, 7.2, 1.3 Hz, 1 Harom), 7.34 (br t, J = ~7.3 Hz, 1 Harom), 7.28
(br t, J = ~8.5 Hz, 1 Harom), 6.10 (s, 1 H, =CH), 2.55 (m, 2 H, CH2),
1.69 (m, 2 H, CH2), 1.56 (s, 9 H, t-C4H9), 1.32 (m, 8 H, CH2), 0.86
(J = 6.9 Hz, 3 H, CH3).
N-Oxide 5 (0.621 g, 1.87 mmol) gave 1a (0.390 g, 80%), N-oxide
11 (0.390 g, 1.08 mmol) gave 1a (0.239 g, 85%), N-oxide 18 (0.210
g, 0.636 mmol) gave 1a (0.117 g, 71%), and 4(1H)-quinolone 12
(0.400 g, 1.21 mmol) gave 1a (0.250 g, 80%).
IR (ATR): 2926, 2853, 2400 (br), 1732 (br), 1590, 1548, 1451,
1404, 1342, 1266, 1177, 1151, 1120, 1022, 931 cm–1.
13C NMR (CDCl3): d = 177.3, 152.3, 150.9, 139.4, 132.6, 126.6,
125.1, 124.0, 112.3, 108.4, 88.3, 31.6, 30.8, 29.1, 28.8, 27.5, 27.3,
22.6, 14.0.
1H NMR (MeOH-d4): d = 8.26 (dd, J = 8.3, 1.5 Hz, 1 Harom), 8.09
(br d, J = 8.6, 1 Harom), 7.84 (ddd, J = 8.2, 7.1, 1.5 Hz, 1 Harom), 7.50
(ddd, J = 8.3, 7.1, 1.0 Hz, 1 Harom), 6.34 (s, 1 H, =CH), 2.92 (t,
J = 7.7 Hz, 2 H, CH2), 1.78 (quint, J = 7.7 Hz, 2 H, CH2), 1.51–1.27
(m, 8 H, CH2), 0.91 (t, J = 6.9 Hz, 3 H, CH3).
13C NMR (MeOH-d4): d = 174.0 (C=O, from HMBC), 156.5, 142.0,
133.7, 126.0, 125.9, 125.4, 116.8, 107.5, 32.9, 32.6, 30.4, 30.1,
28.9, 23.7, 14.4.
Anal. Calcd for C21H29NO4: C, 70.17; H, 8.13; N, 3.90. Found: C,
70.37; H, 8.21; N, 3.81.
4-(Dimethylaminocarbonyloxy)-2-heptylquinoline (17)
4(1H)-Quinolone 3 (0.245 g, 1.01 mmol) was converted into car-
bamate 17 in analogy to the preparation of carbonate 4, using N,N-
dimethylcarbamoyl chloride (0.118 g, 0.10 mL, 1.1 mmol, 1.1
equiv) and stirring the mixture for 2 h (TLC: EtOAc). The crude
product was purified by flash chromatography (hexanes–EtOAc,
1:5, TLC: EtOAc, Rf = 0.79) to yield carbamate 17 (0.292 g, 92%)
as an oil.
Acknowledgment
We thank the Fonds zur Förderung der wissenschaftlichen For-
schung (Project P14985-N03) for financial support and S. Felsinger
for recording the NMR spectra.
IR (Si): 2927, 2856, 1733, 1622, 1604, 1505, 1390, 1373, 1350,
1150 cm–1.
1H NMR (CDCl3): d = 8.02 (br d, J = 8.4 Hz, 1 Harom), 7.92 (dd,
J = 8.2, 1.3 Hz, 1 Harom), 7.65 (ddd, J = 8.4, 6.8, 1.3 Hz, 1 Harom),
7.45 (ddd, J = 8.2, 6.8, 1.0 Hz, 1 Harom), 7.25 (s, 1 H, =CH), 3.22 (s,
3 H, NCH3), 3.06 (s, 3 H, NCH3), 2.93 (m, 2 H, CH2), 1.79 (m, 2 H,
CH2), 1.43–1.20 (m, 8 H, CH2), 0.85 (t, J = 6.8 Hz, 3 H, CH3).
13C NMR (CDCl3): d = 164.1, 154.8, 153.3, 149.6, 129.6, 128.8,
125.6, 121.2, 121.0, 112.3, 39.6, 36.9, 36.6, 31.7, 29.9, 29.5, 29.1,
22.6, 14.0.
References
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Anal. Calcd for C19H26N2O2: C, 72.58; H, 8.33; 8.91. Found: C,
72.49; H, 8.25; N, 8.80.
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A solution of carbamate 17 (0.265 g, 0.843 mmol) and MCPBA
(0.200 g, 77%, 0.893 mmol) in anhyd CH2Cl2 (4 mL) was stirred for
1 h at r.t. (TLC: Et2O). The mixture was concentrated under reduced
pressure and the residue was purified by flash chromatography
(EtOAc, Rf = 0.39) to give N-oxide 18 (0.250 g, 90%) as colorless
needles; mp 71–72 °C (1,2-C2H4Cl2–i-Pr2O, 30 °C → –17 °C).
IR (Si): 2928, 2856, 1733, 1362, 1212, 1154, 1083 cm–1.
1H NMR (CDCl3): d = 8.77 (br d, J = 8.6 Hz, 1 Harom), 7.92 (dd,
J = 8.3, 1.4 Hz, 1 Harom), 7.74 (ddd, J = 8.6, 6.8, 1.4 Hz, 1 Harom),
7.58 (ddd, J = 8.3, 6.8, 1.1 Hz, 1 Harom), 7.27 (s, 1 H, =CH), 3.24 (s,
3 H, NCH3), 3.09 (m, 2 H, CH2), 3.07 (s, 3 H, NCH3), 1.79 (m, 2 H,
CH2), 1.44 (m, 2 H, CH2), 1.35 (m, 2 H, CH2), 1.28 (m, 4 H, CH2),
0.85 (s, 3 H, CH3).
13C NMR (CDCl3): d = 153.3, 149.7, 144.5, 142.2, 130.6, 127.7,
123.3, 121.9, 120.2, 113.8, 37.0, 36.7, 31.74, 31.7, 29.6, 29.0, 26.1,
22.6, 14.0.
Anal. Calcd for C19H26N2O3: C, 69.06; H, 7.93; N, 8.48. Found: C,
69.02; H, 7.89; N, 8.52.
Synthesis 2007, No. 10, 1517–1522 © Thieme Stuttgart · New York

1522
A. Woschek et al.
PAPER
(20) Katzenellenbogen, J. A.; Utawanit, T. J. Am. Chem. Soc.
(16) Mikenda, W. Vib. Spectrosc. 1992, 3, 327.
(17) Bruker programs: SMART, version 5.629; SAINT, version
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(18) Sheldrick, G. M. SHELX97: Program System for Crystal
Structure Determination; University of Göttingen:
Germany, 1997.
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(21) CCDC 616835-616836 contains the supplementary
crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data.requecst/cif.
(19) Epstein, J.; Cannon, P. Jr.; Swidler, R.; Baraze, A. J. Org.
Chem. 1977, 42, 759.
Synthesis 2007, No. 10, 1517–1522 © Thieme Stuttgart · New York