Synthesis of novel 1-hydroxyquinolones with high anti-toxoplasma activity

Article abstract of DOI:10.3987/COM-10-S(E)9

All for the treatment of malaria and toxoplasmosis the novel hydroxyquinolones 2-5 were prepared by reaction of aniline and hydroxyaniline, respectively and the β-ketoesters 10a-c. As products the quinolones 8 and 15, respectively were obtained. Benzylation, oxidation and hydrogenation then led to the desired substances. Compound 2 has a similar anti-malaria activity as the approved drug Atovaquone. The Japan Institute of Heterocyclic Chemistry.

Full text of DOI:10.3987/COM-10-S(E)9

HETEROCYCLES, Vol. 82, No. 1, 2010
377
HETEROCYCLES, Vol. 82, No. 1, 2010, pp. 377 - 396. © The Japan Institute of Heterocyclic Chemistry
Received, 28th February, 2010, Accepted, 7th May, 2010, Published online, 10th May, 2010
DOI: 10.3987/COM-10-S(E)9
SYNTHESIS OF NOVEL 1-HYDROXYQUINOLONES WITH HIGH
ANTI-TOXOPLASMA ACTIVITY
Lutz F. Tietze* and Ling Ma
Institute of Organic and Biomolecular Chemistry, Georg-August-University
Goettingen, Tammannstraße 2, D-37077 Goettingen, Germany. E-mail:
ltietze@gwdg.de, FAX: +49 (0)551 399476
Abstract – All for the treatment of malaria and toxoplasmosis the novel
hydroxyquinolones 2–5 were prepared by reaction of aniline and hydroxyaniline,
respectively and the β-ketoesters 10a-c. As products the quinolones 8 and 15,
respectively were obtained. Benzylation, oxidation and hydrogenation then led to
the desired substances. Compound 2 has a similar anti-malaria activity as the
approved drug Atovaquone.
INTRODUCTION
The 1-hydroxyquinolone HDQ (1) containing a dodecyl side chain at C-2 shows a strong inhibitory
activity against parasite replication of Toxoplasma gondi and Plasmodium falciparum in tissue culture.1
These widespred humanes pathogens cause toxoplasmosis and malaria, respectively. The mode of action
of 1 seems to be an inhibition of ubiquinol binding enzymes. Recently, it has been shown that HDQ (1) is
a high affinity inhibitor for the T. gondi alternative NADH dehydrogenase (TgNDH2-I).2 In this species 1
causes a rapid loss of the mitochondrial membrane potential followed by the decrease of ATP
concentration, whereas in P. falciparum the de novo synthesis of pyrimidin is affected. Here we describe
the synthesis of the 1-hydroxyquinolones 2-5 (Scheme 1), of which the new compound 2 is up to ten
times more active than HDQ in cell culture3 and almost match the activity of the approved antimalaria
drug Atovaquone.4 Moreover, compound 2 as well as compound 3 caused a significant reduction of
inflammatory foci in mice.
This paper is dedicated to Prof. Dr. Albert Eschenmoser on the occasion of his 85th birthday.

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HETEROCYCLES, Vol. 82, No. 1, 2010
O
O
O
Me
nC12H25
N
nC12H25
N
nC12H25
N
Me
OH
OH
OH
1
2
3
NMe2
NMe2
O
O
O
O
nC12H25
N
Me
N
nC12H25
OH
OH
4
5
Scheme 1. Structures of HDQ (1) and 1-hydroxyquinolone 2-5.
The hydroxyquinolone 2 contains an extra methyl group at C-3 in comparison to HDQ, whereas in 3 the
two alkyl groups at C-2 and C-3 are exchanged.5 Compounds 4 and 5 have an additional
dimethylaminoethoxy group, which was introduced to improve their water solubility. However, these
substances show a much lower activity against P. gondi compared with 2 and 3. This could be traced back
to a reduced penetration of these compounds through the cell wall of the parasites.
RESULTS AND DISCUSSION
OBn
O
OBn
R2
R1
R2
R1
R2
R1
N
O
N
N
OH
2: R1 = nC12H25, R2 = Me
3: R1 = Me, R2 = nC12H25
6
7
O
O
O
R2
R1
+
R1
OEt
NH2
R2
N
H
8
9
10
Scheme 2. Retrosynthetic analysis of 1-hydroxyquinolones 2 and 3.

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379
Several syntheses of hydroxyquinolones are known6 and the most common follows the retrosynthetic
analysis shown in Scheme 2, where the hydroxyl group is introduced as one of the last steps by oxidation
of the nitrogen atom in the quinoline 7. Thus, compounds 2 and 3 lead via 6 to the quinoline 7, which is
accessible via 8 by a Conrad-Limpach cyclization7 using aniline (9) and substituted acetoacetates (10).
According to this scheme, 2 and 3 could be obtained from aniline and ethyl acetoacetate (11) in four steps
(Scheme 3). For the synthesis of 2 and 3, ethyl acetoacetate was transformed into the esters 10a and 10b,
respectively using known procedures.8 The following Conrad-Limpach cyclizations were carried out in a
two-step fashion7,9: treatment of aniline and 10a as well as 10b under the given conditions (Scheme 3) led
to the corresponding enamines, which on reflux in diphenyl ether at 260 °C gave the quinolones 8a and
8b, respectively in moderate yield. It followed the formation of the corresponding enolates with LDA in
DMSO,10 which were benzylated using benzyl bromide to give the protected quinolines 7a and 7b in 80%
and 78% yield, respectively. Interestingly, employing LDA in THF as solvent followed by an alkylation
with benzyl bromide or TIPSCl or TIPSOTf11 failed completely. For the following oxidation we used
mCPBA in dichloromethane and the removal of the benzyl protecting group by hydrogenolysis to give the
desired 1-hydroxyquinolones 2 and 3, respectively was achieved under mild conditions with Pd/C under a
hydrogen atmosphere in ethanol at ambient pressure.
O
O
O
10a: a
10b: b
10a: c
10b: d
R2
R1
O
O
R1
OEt
OEt
R2
10
N
H
11
8
8a: e
8b: f
O
OBn
R2
R1
R2
R1
g
N
N
OH
a: R1 = nC12H25, R2 = Me
b: R1 = Me, R2 = nC12H25
2: 81%
3: 77%
7
Scheme 3. Synthesis of 1-hydroxyquinolone 2 and 3; (a) 1) LDA, THF, –78 °C, 1 h, 1-bromoundecane,
rt, 1.5h; 2) NaH, THF, 0 °C, 15 min, MeI, rt, 16 h, 42% from 11; (b) NaOEt, 1-bromododecane, EtOH,
80 °C, 6 h, 65%; (c) 1) aniline, p-TsOH, benzene, Dean-Stark apparatus, 80 °C, 42 h; 2) Ph2O, 260 °C,
1 h, 25% from 10a; (d) 1) aniline, AcOH, MS 3 Å, EtOH, 70 °C, 44 h; 2) Ph2O, 260 °C, 1 h, 38% from
10b; (e) LDA, DMSO, rt, 1 h, BnBr, rt, 40 min, 80%; (f) LDA, DMSO, rt, 1 h, BnBr, rt, 25 min, 78%; (g)
1) mCPBA, CH2Cl2, rt, 1 h; 2) Pd/C, H2, EtOH, rt, 30 min.

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HETEROCYCLES, Vol. 82, No. 1, 2010
One of the problems in the application of the hydroxyquinolones for treatment is their low water
solubility; we therefore prepared analogues containing a N,N-dimethylaminoethoxy group at C-6. The
synthesis of the desired hydroxyquinolones 4 and 5 was carried out in a smilar way as described for 2 and
3 in 8 steps with an all over yield of 31% for 4 and 25% for 5 (scheme 4).
O
O
O
O
10b: a
10c: b
14b: c
14c: d
R2
R1
TIPSO
R2
R1
EtO
TIPSO
R1
OEt
R2
N
N
H
H
10
14
15
15b: e
15c: f
NMe2
O
OBn
N
OBn
17b: i
17c: j
16b: g
16c: h
R2
R1
TIPSO
R2
R1
OBn
N
HO
R2
R1
N
18
17
16
18b: k
18c: l
O
NMe2
O
NMe2
OBn
O
R2
R1
O
R2
R1
19b: m
19c: n
N
O
N
OH
b: R1 = Me, R2 = nC12H25
c: R1 = nC12H25, R2 = H
19
4
5
Scheme 4. Synthesis of 1-hydroxyquinolone 4 and 5; (a) 13, AcOH, MS 3 Å, EtOH, 75 °C, 42 h, 68%;
(b) 13, AcOH, MS 3 Å, EtOH, 75 °C, 44 h, 89%; (c) Ph2O, 260 °C, 1 h, 82%; (d) Ph2O, 260 °C, 1 h,
79%; (e) LDA, DMSO, rt, 1 h, BnBr, rt, 2 h, 88%; (f) LDA, DMSO, rt, 1.25 h, BnBr, rt, 45 min, 71%; (g)
TBAF, THF, 0 °C, 1 h, rt, 2 h, 98%; (h) TBAF, THF, 0 °C, 1 h, rt, 3.5 h, 90%; (i) NaH, DMF, rt, 1 h,
Me2NCH2CH2Cl·HCl, 100 °C, 2 h, 95%; (j) NaH, DMF, rt, 1 h, Me2NCH2CH2Cl·HCl, 100 °C, 2 h, 98%;
(k) mCPBA, CH2Cl2, rt, 1.5 h, 80%; (l) mCPBA, CH2Cl2, rt, 1.5 h, 84%; (m) Pd/C, H2, EtOH, rt, 1.5 h,
89%; (n) Pd/C, H2, EtOH, rt, 1.3 h, 73%.
As starting material 4-hydroxyaniline (12) was used instead of aniline (9). The free hydroxyl group was
protected as TIPS-ether to give 4-triisopropylsilyloxyaniline (13).12 For the Conrad-Limpach cyclization,

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381
13 was treated with 10b and 10c, respectively in the presence of acetic acid to give the corresponding
enamines 14b and 14c which were then cyclized as described for 2 and 3 at 260 °C to give the quinolones
15b and 15c in reasonable yields of 82% and 79% yield, respectively. Benzylation using LDA and benzyl
bromide in DMSO led to the benzyl protected compounds 16b and 16c in 88% and 71% yields
respectively. After removal of the TIPS group with TBAF, the free hydroxyl group in the quinolines 17b
and 17c was deprotonated with sodium hydride and treated with 2-dimethylaminoethyl chloride
hydrochloride in DMF to introduce the N,N-dimethylaminoethoxy group at C-6 position.13 In the
following oxidation of the obtained compounds 18b and 18c using mCPBA in dichloromethane both
nitrogen atoms in the substrates were oxidized to afford the N,N’-dioxides 19b and 19c. As the last step
hydrogenation using Pd/C as catalyst in ethanol led to a reduction of the N-oxide of the
dimethylaminoethoxy group at the C-6 position and concurrently to a hydrogenolysis of the benzyl group
to give the desired 1-hydroxyquinolones 4 and 5. Under the employed conditions, a reduction of second
N-oxide in the molecule was not observed. For the biological tests of the inhibition activity against
parasite replication compounds 2-5 were twice recrystallized from ethanol/acetone for a high purity.
CONCLUSION
Hydroxyquinolone 1 is known as a potent inhibitor of toxoplasmosis and malaria. We have prepared
novel hydroxyquinolones containing different side chains at different positions, which have an up to ten
times increased biological activity with compound 2 nearly matching the potency of the known
antimalaria drug Atovaquone (IC50 values: HDQ = 4.2  1.5 nM, 2 = 0.4  0.1 nM, 3 = 0.8  0.1 nM). In
contrast, compounds 4 and 5 containing a tertiary amino functionality to improve their water solubility by
formation of a salt show a reduced activity probably due to a decreased penetration through the cell wall
of the parasites.
EXPERIMENTAL
General: All reactions were performed in flame-dried glassware under an atmosphere of argon and the
reactants were introduced by syringe. Solvents were dried and purified purified according to the method
defined by Perrin and Armarego.14 Commercial reagents were used without further purification.
Thin-layer chromatography (TLC) was carried out on precoated Alugram SIL G/UV254 (0.25 mm) plates
from Macherey–Nagel & Co. Column chromatography was carried out on silica gel 60 from Merck with
particle size 0.063–0.200 mm for normal pressure and 0.040–0.063 mm for flash chromatography.
Melting points were recorded on a Mettler FP61 and are uncorrected. IR spectra were determined on a
Bruker Vektor 22 (KBr pellets or films), UV/Vis spectra on a Perkin–Elmer Lambda 2 (MeCN), and mass
spectra on a Finnigan MAT 95 (for EI-MS, EI-HRMS, DCI) and a Bruker Daltronik Apex IV (for

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1
ESI-HRMS). H-NMR spectra were recorded either on a Varian Mercury 300, Unity 300 or Inova 600
spectrometer. 13C-NMR spectra were recorded at 75, 125 or 150 MHz. Spectra were taken at room
temperature in deuterated solvents as indicated using the solvent peak or TMS as internal standard.
Synthesis of 2-dodecyl-1-hydroxy-3-methyl-4-quinolone (2)
Ethyl 3-oxopentadecanoate (10c): To a solution of LDA, prepared from i-Pr2NH (24.7 mL, 0.175 mol)
and n-BuLi (72.8 mL, 0.182 mol; 2.5 M in hexanes), in dry THF (150 mL) at –78 °C was added ethyl
acetoacetate (9.11 g, 70.0 mmol) and the suspension was stirred at –78 °C for 1 h. Afterwards
1-bromoundecane (1.20 mL, 70.0 mmol) was added at 0 °C and the solution was stirred at room
temperature for 1.5 h. The solution was neutralized with 2 M hydrochloric acid and extracted with Et2O
(3 × 120 mL). The combined organic extracts were washed with brine (2 × 270 mL), dried over Na2SO4
and concentrated under reduced pressure. Purification of the residue by flash chromatography
(pentane/EtOAc, 20:1) provided 10c (9.80 g, 49%) as a yellowish solid. Rf = 0.37 (pentane/EtOAc, 20:1).
1H-NMR (300 MHz, CDCl3): δ = 0.88 (t, J = 7.2 Hz, 3 H, 15-H3), 1.221.38 (m, 21 H, 6-H2 to 14-H2,
OCH2CH3), 1.52–1.64 (m, 2 H, 5-H2), 2.54 (t, J = 7.2 Hz, 2 H, 4-H2), 3.42 (s, 2 H, 2-H2), 4.19 (q,
J = 7.2 Hz, 2 H, OCH2CH3) ppm. 13C-NMR (125 MHz, CDCl3): δ = 14.08 (C-15, OCH2CH3), 22.66
(C-14), 23.46 (C-5), 29.01, 29.32, 29.33, 29.42, 29.56, 29.60, 29.62 (C-6 to C-12), 31.89 (C-13), 43.03
(C-4), 49.30 (C-2), 61.30 (OCH2CH3), 167.2 (C-1), 202.9 (C-) ppm. IR (KBr): ̃ = 2917, 2850, 1742,
1710, 1468, 1411, 1367, 1329, 1272, 1166, 1095, 1033, 717, 651 cm-1. UV (CH3CN): λmax (lg ) = 221.5
(2.661), 246.0 nm (2.714). MS (70 eV, EI): m/z (%) = 284.4 (7) [M]+, 197.3 (7) [MCH2COOEt+H]+,
130.1 (100) [Mn-C11H23+H]+. HRMS (ESI): calcd. for C17H32O3 + H+ 285.2424; found 285.2424.
Ethyl 2-methyl-3-oxopentadecanoate (10a): Sodium hydride (1.56 g, 38.8 mmol, 60% in mineral oil)
was added slowly to a solution of 10c (10.0 g, 35.3 mmol) in THF (35 mL) at 0 °C. After stirring for
15 min at 0 °C iodomethane (6.01 g, 42.3 mmol) was added and the solution was stirred at room
temperature for 16 h. The reaction was quenched by addition of H2O (10 mL), the layers were separated
and the aqueous layer was extracted with EtOAc (4 × 30 mL). The combined organic extracts were dried
over Na2SO4 and concentrated under reduced pressure. Purification of the residue by flash
chromatography (pentane/EtOAc, 20:1) provided 10a (8.95 g, 85%) as a yellow oil. Rf = 0.41
(pentane/EtOAc, 20:1). 1H-NMR (300 MHz, CDCl3): δ = 0.88 (t, J = 7.2 Hz, 3 H, 15-H3), 1.181.38 (m,
24 H, 6-H2 to 14-H2, OCH2CH3, 2-CH3), 1.52–1.63 (m, 2 H, 5-H2), 2.402.62 (dt, J = 12.0, 7.2 Hz, 2 H,
4-H2), 3.50 (q, J = 7.2 Hz, 1 H, 2-H), 4.19 (q, J = 7.2 Hz, 2 H, OCH2CH3) ppm. 13C-NMR
(125 MHz, CDCl3): δ = 12.74 (2-CH3), 14.05, 14.07 (C-15, OCH2CH3), 22.65 (C-14), 23.53 (C-5), 29.06,

HETEROCYCLES, Vol. 82, No. 1, 2010
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29.30, 29.35, 29.43, 29.56, 29.59, 29.61 (C-6 to C-12), 31.88 (C-13), 41.33 (C-4), 52.85 (C-2), 61.22
(OCH2CH3), 170.6 (C-1), 205.9 (C-) ppm. IR (film):  = 2925, 2854, 1745, 1717, 1464, 1376, 1324,
̃
1242, 1192, 1118, 860 cm-1. UV (CH3CN): λmax (lg ) = 258.0 nm (2.754). MS (ESI): m/z (%) = 299.2
(78) [M+H]+, 321.2 (100) [M+Na]+, 619.5 (80) [2M+Na]+. HRMS (ESI): calcd. for C18H34O3 + H+
299.2580; found 299.2582.
2-Dodecyl-3-methyl-4-quinolone (8a): Ester 10a (8.10 g, 27.1 mmol) and p-toluenesulfonic acid (0.6 g)
were added to a solution of aniline (4.04 g, 43.4 mmol) in benzene (450 mL) using a Dean-Stark
apparatus. After stirring for 42 h at 80 °C the precipitate was separated by filtration through celite, which
was rinsed with EtOH (300 mL), the filtrate was then concentrated under reduced pressure. The brown
liquid residue was added dropwise to refluxing diphenyl ether (70 g) and the formed EtOH was removed
by distillation. After stirring for 1 h at 260 °C and cooling to room temperature, diphenyl ether was
evaporated under reduced pressure (20 mbar, 80 °C), n-pentane (80 mL) was added and the formed solid
separated by filtration and recrystallized from EtOH/acetone to give 8a (2.18 g, 25%) as a yellow solid.
1
Rf = 0.29 (CH2Cl2/MeOH, 95:5); m.p. 173 °C. H-NMR (600 MHz, DMSO-d6, 35 °C): δ = 0.88 (t,
J = 7.2 Hz, 3 H, 12´-H3), 1.201.40 (m, 18 H, 3´-H2 to 11´-H2), 1.63 (m, 2 H, 2´-H2), 1.98 (s, 3 H, 3-CH3),
2.66 (t, J = 7.8 Hz, 2 H, 1´-H2), 7.22 (t, J = 8.4 Hz, 1 H, 6-H), 7.48 (d, J = 8.4 Hz, 1 H, 8-H), 7.57 (t,
J = 8.4 Hz, 1 H, 7-H), 8.04 (d, J = 8.4 Hz, 1 H, 5-H), 11.26 (sbr, 1 H, NH) ppm. IR (KBr): ̃ = 3060, 2919,
2850, 1638, 1607, 1592, 1555, 1501, 1394, 1358, 1258, 1190, 999, 861, 754, 693, 604, 572, 539,
434 cm-1. UV (MeOH): λmax (lg ) = 213.0 (4.400), 239.5 (4.490), 322.0 (4.056), 334.5 nm (4.066). MS
(ESI): m/z (%) = 328.2 (100) [M+H]+, 655.5 (7) [2M+H]+. HRMS (ESI): calcd. for C22H33NO + H+
328.2634; found 328.2636.
4-Benzyloxy-2-dodecyl-3-methylquinoline (7a): To a solution of LDA, prepared from i-Pr2NH
(0.65 mL, 4.6 mmol) and n-BuLi (2.0 mL, 5.0 mmol; 2.5 M in hexanes), in dry THF (7 mL) at room
temperature was added a suspension of 8a (1.5 g, 4.6 mmol) in DMSO (160 mL) and the solution was
stirred at room temperature for 1 h. Afterwards benzyl bromide (1.1 mL, 9.2 mmol) was added and the
solution was stirred at room temperature for 40 min. The reaction was quenched by addition of brine
(450 mL) and the mixture extracted with EtOAc (3 × 340 mL). The combined organic extracts were
washed with brine (3 × 400 mL), dried over Na2SO4 and concentrated under reduced pressure.
Purification of the residue by flash chromatography (pentane/EtOAc, 10:1) provided 7a (1.50 g, 80%) as
a yellow solid. Rf = 0.41 (pentane/EtOAc, 8:1). 1H-NMR (300 MHz, CDCl3): δ = 0.85 (t, J = 7.2 Hz, 3 H,
12´-H3), 1.20–1.52 (m, 18 H, 3´-H2 to 11´-H2), 1.75 (m, 2 H, 2´-H2), 2.37 (s, 3 H, 3-CH3), 2.96 (t, 2 H,
J = 7.8 Hz, 1´-H2), 5.03 (s, 2 H, -CH2Ph), 7.35–7.54 (m, 6 H, 6-H, 5 × Ph-H), 7.98 (dd, J = 2 × 8.4 Hz,

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HETEROCYCLES, Vol. 82, No. 1, 2010
1 H, 7-H), 7.98 (m, 2 H, 5-H, 8-H) ppm. 13C-NMR (125 MHz, CDCl3): δ = 11.93 (3-CH3), 14.09 (C-12´),
22.67 (C-11´), 29.03, 29.33, 29.55, 29.59, 29.63, 29.64, 29.66, 29.88, 31.90, 37.10 (C-1´ to C-10´), 75.95
(-CH2Ph), 121.2, 122.4 (C-3, C-4a), 121.6 (C-5), 125.4 (C-6), 127.9 (2  Ph-Co), 128.3, 128.5, 128.9 (C-7,
C-8, Ph-Cp), 128.6 (2  Ph-Cm), 136.7 (Ph-Ci), 147.9 (C-8a), 159.5, 164.3 (C-2, C-4) ppm. IR (KBr): ̃ =
3060, 2914, 2847, 1618, 1600, 1558, 1491, 1468, 1454, 1393, 1353, 1216, 1170, 1105, 1072, 1026, 1005,
965, 913, 752, 735, 707, 694, 616 cm-1. UV (CH3CN): λmax (lg ) = 225.0 (4.656), 274.0 (3.639), 303.0
(3.349), 316.5 nm (3.360). MS (70 eV, EI): m/z (%) = 417.5 (4) [M]+, 263.3 (63) [Mn-C11H23+H]+, 91.1
(100) [CH2Ph]+. HRMS (ESI): calcd. for C29H39NO + H+ 418.3104; found 418.3104.
2-Dodecyl-1-hydroxy-3-methyl-4-quinolone (2): A solution of m-chloroperbenzoic acid (0.990 g,
4.03 mmol, 70%) in CH2Cl2 (105 mL) was added to a solution of 7a (1.40 g, 3.35 mmol) in CH2Cl2
(220 mL). After stirring for 1 h at room temperature, the solution was washed with saturated aq. NaHCO3
(2 × 310 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was dissolved in
EtOH (270 mL), Pd/C (10%, 100 mg) was added, and after applying an H2 atmosphere (1 bar), the solution
was stirred at room temperature for 30 min. After filtration through celite, which was thoroughly rinsed
with EtOH (270 mL), the filtrate was concentrated under reduced pressure and the residue recrystallised
from EtOH/acetone to give 2 (0.93 g, 81%) as a colorless solid. Rf = 0.31 (CH2Cl2/MeOH, 95:5).
1H-NMR (300 MHz, CDCl3): δ = 0.88 (t, J = 7.2 Hz, 3 H, 12´-H3), 1.17–1.43 (m, 18 H, 3´-H2 to 11´-H2),
1.59 (m, 2 H, 2´-H2), 2.02 (s, 3 H, 3-CH3), 2.86 (t, J = 7.8 Hz, 2 H, 1´-H2), 6.98 (dd, J = 2 × 8.4 Hz, 1 H,
6-H), 7.28 (dd, J = 2 × 8.4 Hz, 1 H, 7-H), 7.78 (d, J = 8.4 Hz, 1 H, 8-H), 7.97 (d, J = 8.4 Hz, 1 H, 5-H),
10.86 (sbr, 1 H, OH) ppm. 13C-NMR (125 MHz, CDCl3): δ = 11.46 (3-CH3), 14.10 (C-12´), 22.68 (C-11´),
27.50, 29.00, 29.29, 29.35, 29.58, 29.64, 29.67, 29.89 (C-1´ to C-9´), 31.92 (C-10´), 114.5 (C-3), 115.5
(C-8), 122.8 (C-4a), 123.7 (C-6), 124.6 (C-5), 131.0 (C-7), 139.0 (C-8a), 153.5 (C-2), 172.2 (C-4) ppm.
IR (KBr): ̃
= 2921, 2850, 1587, 1397, 1339, 1014, 755, 479, 435 cm-1. UV (MeOH): λmax (lg ) = 214.5
(4.373), 249.5 (4.353), 336.5 (3.889), 347.0 nm (3.889). MS (ESI): m/z (%) = 344.2 (100) [M+H]+, 687.5
(38) [2M+H]+, 1030.7 (13) [3M+H]+. HRMS (ESI): calcd. for C22H33NO2 + H+ 344.2584; found
344.2584.
Synthesis of 3-dodecyl-1-hydroxy-2-methyl-4-quinolone (3)
Ethyl 2-dodecylacetoacetate (10b): Sodium (2.87 g, 0.125 mol) was added to EtOH (50 mL) and the
suspension was stirred for 30 min at room temperature. Afterwards ethyl acetoacetate (14.9 g, 0.115 mol)
and 1-bromododecane (26.0 g, 0.104 mol) were added dropwise. After stirring at 80 °C for 6 h the
solution was concentrated under reduced pressure, ice-water (180 mL) was added, the layers were

HETEROCYCLES, Vol. 82, No. 1, 2010
385
separated and the aqueous layer was extracted with Et2O (20 mL). The combined organic extracts were
dried over Na2SO4 and concentrated under reduced pressure. Purification of the residue by flash
chromatography (pentane/Et2O, 4:1) provided 10b (20.3 g, 65%) as a colorless oil. Rf = 0.49
1
(pentane/Et2O, 4:1). H-NMR (300 MHz, CDCl3): δ = 0.88 (t, J = 7.2 Hz, 3 H, 14-H3), 1.181.36 (m,
23 H, 4-H2 to 13-H2, OCH2CH3), 1.85 (m, 2 H, 3-H2), 2.22 (s, 3 H, 2-COCH3), 3.40 (t, J = 7.8 Hz, 1 H,
2-H), 4.19 (q, J = 7.2 Hz, 2 H, OCH2CH3) ppm. 13C-NMR (75 MHz, CDCl3): δ = 14.08 (C-14,
OCH2CH3), 22.66, 27.37, 28.19, 29.29, 29.31, 29.49, 29.57, 29.60, 29.61, 31.88 (C-3 to C-13), 28.67
(2-COCH3), 59.94 (C-), 61.23 (OCH2CH3), 169.9 (C-1), 203.4 (2-COCH3) ppm. IR (film): ̃ = 2925,
2854, 1743, 1718, 1466, 1358, 1242, 1150, 1026 cm-1. UV (CH3CN): λmax (lg ) = 256.0 nm (2.941). MS
(70 eV, EI): m/z (%) = 298.4 (3) [M]+, 256.3 (42) [MCH3CO+H]+, 130.1 (100) [Mn-C12H25+H]+, 43.1
(27) [CH3CO]+. HRMS (ESI): calcd. for C18H34O3 + H+ 299.2580; found 299.2580.
3-Dodecyl-2-methyl-4-quinolone (8b): Ester 10b (10.0 g, 33.5 mmol), molecular sieves 3 Å (6.62 g) and
acetic acid (0.29 mL) were added to a solution of aniline (5.00 g, 53.7 mmol) in EtOH (200 mL). After
stirring for 44 h at 70 °C the precipitate was separated by filtration through celite, which was thoroughly
rinsed with EtOH (200 mL), and the filtrate was concentrated under reduced pressure. The brown liquid
residue was added dropwise to refluxing diphenyl ether (150 g) and the formed EtOH was removed by
distillation. After stirring for 1 h at 260 °C and cooling to room temperature, diphenyl ether was
evaporated under reduced pressure (20 mbar, 80 °C), n-pentane (150 mL) was added and the formed solid
was separated by filtration and recrystallized from EtOH/acetone to give 8b (4.16 g, 38%) as a colorless
1
solid. Rf = 0.31 (CH2Cl2/MeOH, 95:5). H-NMR (300 MHz, CD3OD): δ = 0.88 (t, J = 7.2 Hz, 3 H,
12´-H3), 1.201.43 (m, 18 H, 3´-H2 to 11´-H2), 1.50 (m, 2 H, 2´-H2), 2.50 (s, 3 H, 2-CH3), 2.64 (t,
J = 7.8 Hz, 2 H, 1´-H2), 7.32 (dd, J = 2 × 8.4 Hz, 1 H, 6-H), 7.48 (d, J = 8.4 Hz, 1 H, 8-H), 7.61 (dd,
13
J =2 × 8.4 Hz, 1 H, 7-H), 8.20 (d, J = 8.4 Hz, 1 H, 5-H) ppm. C-NMR (125 MHz, CD3OD): δ = 14.42
(C-12´), 18.08 (2-CH3); 23.73 (C-11´), 26.39, 30.11, 30.46, 30.73, 30.76, 30.77, 30.97, 33.07 (C-1´ to
C-10´), 118.5 (C-8), 121.7 (C-4a), 124.4 (C-6), 124.9 (C-2), 126.2 (C-5), 132.5 (C-7), 140.5 (C-8a), 149.1
(C-3), 178.8 (C-4) ppm. IR (KBr): ̃ = 2919, 2849, 1639, 1606, 1592, 1555, 1500, 1358, 1255, 1023, 753,
721, 698, 601, 569, 448 cm-1. UV (MeOH): λmax (lg ) = 213.0 (4.414), 240.0 (4.461), 245.5 (4.451),
322.5 (4.033), 335.0 nm (4.033). MS (ESI): m/z (%) = 328.2 (100) [M+H]+, 655.5 (16) [2M+H]+. HRMS
(ESI): calcd. for C22H33NO + H+ 328.2634; found 328.2635.
4-Benzyloxy-3-dodecyl-2-methylquinoline (7b): To a solution of LDA, prepared from i-Pr2NH
(0.43 mL, 3.1 mmol) and n-BuLi (1.3 mL, 3.4 mmol; 2.5 M in hexanes), in dry THF (2 mL) at room
temperature was added a suspension of 8b (1.0 g, 3.1 mmol) in DMSO (100 mL) and the solution was

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HETEROCYCLES, Vol. 82, No. 1, 2010
stirred at room temperature for 1 h. Afterwards benzyl bromide (0.72 mL, 6.1 mmol) was added and the
solution was stirred at room temperature for 25 min. The reaction was quenched by addition of brine
(300 mL) and the mixture extracted with EtOAc (3 × 200 mL). The combined organic extracts were
washed with brine (3 × 200 mL), dried over Na2SO4 and concentrated under reduced pressure.
Purification of the residue by flash chromatography (pentane/EtOAc, 4:1) provided 7b (1.01 g, 78%) as a
1
yellow oil. Rf = 0.50 (pentane/EtOAc, 3:1). H-NMR (300 MHz, CDCl3): δ = 0.85 (t, J = 7.2 Hz, 3 H,
12´-H3), 1.201.43 (m, 18 H, 3´-H2 to 11´-H2), 1.55 (m, 2 H, 2´-H2), 2.702.80 (m, 5 H, 2-CH3, 1´-H2),
5.08 (s, 2 H, -CH2Ph), 7.337.64 (m, 7 H, 6-H, 7-H, 5 × Ph-H), 7.98 (d, J = 8.4 Hz, 2 H, 5-H, 8-H) ppm.
13C-NMR (125 MHz, CDCl3): δ = 14.19 (C-12´), 22.76 (C-11´), 23.67 (2-CH3), 26.85, 29.42, 29.46,
29.67, 29.72, 29.73, 29.99, 30.08, 31.99 (C-1´ to C-10´), 76.68 (-CH2Ph), 121.9 (C-5), 122.7 (C-3), 125.5
(C-6), 126.8 (C-4a), 127.6 (2  Ph-Co), 128.3, 128.7, 128.8, (C-7, C-8, Ph-Cp), 128.7 (2  Ph-Cm), 137.0
(Ph-Ci), 148.0 (C-8a), 159.7, 160.5 (C-2, C-4) ppm. IR (film): ̃ = 2924, 2853, 1592, 1562, 1493, 1455,
1402, 1363, 1346, 1208, 1122, 1106, 1059, 1004, 765, 733, 696 cm-1. UV (CH3CN): λmax (lg ) = 226.0
(4.757), 273.5 (3.738), 303.0 (3.441), 316.5 nm (3.459). MS (ESI): m/z (%) = 418.3 (100) [M+H]+.
HRMS (ESI): calcd. for C29H39NO + H+ 418.3104; found 418.3102.
3-Dodecyl-1-hydroxy-2-methyl-4-quinolone (3): A solution of m-chloroperbenzoic acid (1.57 g,
6.37 mmol, 70%) in CH2Cl2 (160 mL) was added to a solution of 7b (2.22 g, 5.31 mmol) in CH2Cl2
(320 mL). After stirring for 1 h at room temperature the solution was washed with saturated aq. NaHCO3
(2 × 500 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was dissolved in
EtOH (400 mL), Pd/C (10%, 100 mg) was added, and after applying an H2 atmosphere (1 bar), the solution
was stirred at room temperature for 30 min. After filtration through celite, which was thoroughly rinsed
with EtOH (400 mL), the filtrate was concentrated under reduced pressure and the residue recrystallised
from EtOH/acetone to give 3 (1.40 g, 77%) as a colorless solid. Rf = 0.32 (CH2Cl2/MeOH, 95:5); m.p.
145 °C. 1H-NMR (300 MHz, DMSO-d6): δ = 0.88 (t, J = 7.2 Hz, 3 H, 12´-H3), 1.151.45 (m, 20 H, 2´-H2
to 11´-H2), 2.48 (s, 3 H, 2-CH3), 2.55 (t, J = 7.8 Hz, 2 H, 1´-H2), 7.26 (dd, J = 2 × 8.4 Hz, 1 H, 6-H), 7.62
(dd, J = 2 × 8.4 Hz, 1 H, 7-H), 7.78 (d, J = 8.4 Hz, 1 H, 8-H), 8.14 (d, J = 8.4 Hz, 1 H, 5-H), 11.38 (sbr,
1 H, OH) ppm. 13C-NMR (125 MHz, DMSO-d6): δ = 13.67 (C-12´), 14.20 (2-CH3), 21.92 (C-11´), 25.43,
28.54, 28.70, 28.86, 28.89, 28.91, 29.10, 31.14 (C-1´ to C-10´), 114.0 (C-8), 115.7 (C-3), 122.2 (C-6),
123.0 (C-4a), 125.0 (C-5), 130.9 (C-7), 139.3 (C-8a), 146.8 (C-2), 173.2 (C-4) ppm. IR (KBr): ̃ = 2921,
2850, 2432, 1591, 1467, 1418, 1347, 1109, 1081, 986, 754, 708, 636, 487, 443 cm-1. UV (MeOH): λmax
(lg ) = 214.5 (4.499), 251.0 (4.421), 337.5 (3.930), 348.5 nm (3.948). MS (ESI): m/z (%) = 344.2 (100)
[M+H]+, 687.5 (7) [2M+H]+. HRMS (ESI): calcd. for C22H33NO2 + H+ 344.2584; found 344.2585.

HETEROCYCLES, Vol. 82, No. 1, 2010
387
Synthesis of 6-[2-(dimethylamino)ethoxy]-3-dodecyl-1-hydroxy-2-methyl-4-quinolone (4)
4-Triisopropylsilyloxyaniline (13): Triisopropylsilyl chloride (11.6 g, 60.0 mmol) was added to a
suspension of 4-hydroxyaniline (4.37 g, 40.0 mmol) and imidazole (4.08 g, 60.0 mmol) in CH2Cl2
(100 mL). After stirring for 26 h at room temperature water (180 mL) was added, the layers were
separated and the aqueous layer was extracted with CH2Cl2 (2 × 310 mL). The combined organic layers
were washed with brine (150 mL), dried over Na2SO4 and concentrated under reduced pressure.
Purification of the residue by flash chromatography (pentane/EtOAc, 4:1, 1% NEt3) provided 13 (10.7 g,
1
100%) as a yellow oil. Rf = 0.20 (pentane/EtOAc, 6:1). H-NMR (300 MHz, CDCl3): δ = 1.08 (d,
J = 6.6 Hz, 18 H, CH(CH3)2), 1.131.30 (m, 3 H, CH(CH3)2), 3.26 (sbr, 2 H, NH2), 6.56 (d, J = 8.4 Hz,
2 H, 2-H, 6-H), 6.70 (d, J = 8.4 Hz, 2 H, 3-H, 5-H) ppm. 13C-NMR (150 MHz, CDCl3): δ = 12.53
(CH(CH3)2), 17.88 (CH(CH3)2), 116.2 (C-2, C-6), 120.3 (C-3, C-5), 139.9 (C-1), 148.6 (C-4) ppm. IR
(film): 
max (lg ) = 197.0 (4.496), 241.5 (3.989), 306.5 nm (3.339). MS (70 eV, EI): m/z (%) = 265.3 (100) [M]+,
̃
= 3348, 2944, 2866, 1611, 1509, 1463, 1250, 1071, 997, 921, 883, 829, 686 cm-1. UV (CH3CN):
λ
222.3 (85) [MC3H7+H]+. HRMS (ESI): calcd. for C15H27NOSi + H+ 266.1934; found 266.1934.
Ethyl 2-dodecyl-3-[4-(triisopropylsilyloxy)phenylamino]-2-butenoate (14b): Ester 10b (7.32 g,
24.5 mmol), molecular sieves 3 Å (6.50 g) and acetic acid (0.30 mL) were added to a solution of 13
(10.4 g, 39.3 mmol) in EtOH (150 mL). After stirring for 42 h at 75 °C the precipitate was separated by
filtration through celite, which was thoroughly rinsed with EtOH (150 mL), and the filtrate was
concentrated under reduced pressure. Purification of the residue by flash chromatography
(pentane/EtOAc, 20:1) provided 14b (9.05 g, 68%) as a brown oil. Rf = 0.51 (pentane/EtOAc, 20:1).
1H-NMR (300 MHz, CDCl3): δ = 0.88 (t, J = 6.6 Hz, 3 H, 14-H3), 1.09 (d, J = 6.6 Hz, 18 H, CH(CH3)2),
1.141.40 (m, 26 H, 4-H2 to 13-H2, CH(CH3)2, OCH2CH3), 1.91 (s, 3 H, 2´-H3), 2.22 (t, J = 7.2 Hz, 2 H,
3-H2), 4.14 (q, J = 6.6 Hz, 2 H, OCH2CH3), 6.78 (d, J = 8.4 Hz, 2 H, 2´´-H, 6´´-H), 6.88 (d, J = 8.4 Hz,
2 H, 3´´-H, 5´´-H), 10.76 (sbr, 1 H, NH) ppm. 13C-NMR (75 MHz, CDCl3): δ = 12.57 (CH(CH3)2), 14.11,
14.57 (OCH2CH3, C-14), 16.34 (C-2´), 17.86 (CH(CH3)2), 22.68 (C-13), 27.27, 29.35, 29.55, 29.63,
29.65, 29.69, 30.54, 31.91 (C-3 to C-12), 58.83 (OCH2CH3), 95.80 (C-2), 120.0 (C-2´´, C-6´´), 126.6
(C-3´´, C-5´´), 133.3 (C-1´´), 153.3, 156.7 (C-1´, C-4´´), 171.0 (C-1) ppm. IR (film): ̃ = 2925, 2854,
1648, 1603, 1509, 1464, 1245, 1164, 1119, 1013, 914, 883, 788, 683 cm-1. UV (CH3CN): λmax (lg ) =
223.0 (3.671), 312.5 nm (4.056). MS (ESI): m/z (%) = 546.4 (100) [M+H]+, 1091.8 (29) [2M+H]+.
HRMS (ESI): calcd. for C33H59NO3Si + H+ 546.4337; found 546.4335.
3-Dodecyl-2-methyl-6-triisopropylsilyloxy-4-quinolone (15b): Ester 14b (8.82 g, 16.2 mmol) was

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added dropwise to refluxing diphenyl ether (100 g) and the formed EtOH was removed by distillation.
After stirring for 1 h at 260 °C and cooling to room temperature, diphenyl ether was evaporated under
reduced pressure (20 mbar, 80 °C) to afford the crude product which was absorbed on silica gel. Elution
with CH2Cl2 (2.5 L) allowed to remove the remaining diphenyl ether and afterwards elution with EtOAc
(1 L) provided the product, which was recrystallised from EtOH/acetone to give 15b (6.65 g, 82%) as
colorless needles. Rf = 0.62 (CH2Cl2/MeOH, 95:5). 1H-NMR (300 MHz, CDCl3): δ = 0.85 (t, J = 7.2 Hz,
3 H, 12´-H3), 0.98 (d, J = 7.2 Hz, 18 H, CH(CH3)2), 1.071.38 (m, 21 H, 3´-H2 to 11´-H2, CH(CH3)2),
1.52 (m, 2 H, 2´-H2), 2.49 (s, 3 H, 2-CH3), 2.68 (t, J = 7.2 Hz, 2 H, 1´-H2), 7.08 (dd, J = 9.0, 2.4 Hz, 1 H,
7-H), 7.56 (d, J = 9.0 Hz, 1 H, 8-H), 7.76 (d, J = 2.4 Hz, 1 H, 5-H), 12.18 (sbr, 1 H, NH) ppm. 13C-NMR
(75 MHz, CDCl3): δ = 12.56 (CH(CH3)2), 14.10 (C-12´), 17.82 (CH(CH3)2), 18.19 (2-CH3), 22.68, 25.86,
29.36, 29.66, 29.70, 30.09, 31.92 (C-1´ to C-11´), 112.5 (C-8), 125.5 (C-7), 119.5, 125.1, 134.6 (C-2,
C-4a, C-5, C-8a), 146.4, 152.0 (C-3, C-6), 176.3 (C-4) ppm. IR (KBr): ̃ = 2923, 2853, 1588, 1547, 1491,
1431, 1365, 1263, 1157, 969, 883, 827, 689, 587 cm-1. UV (MeOH): λmax (lg ) = 217.0 (4.344), 246.0
(4.549), 288.0 (3.472), 300.5 (3.484), 335.5 (3.961), 349.0 nm (3.937). MS (ESI): m/z (%) = 500.3 (100)
[M+H]+, 999.7 (53) [2M+H]+, 1499.1 (19) [3M+H]+. HRMS (ESI): calcd. for C31H53NO2Si + H+
500.3918; found 500.3918.
4-Benzyloxy-3-dodecyl-2-methyl-6-(triisopropylsilyloxy)quinoline (16b): To a solution of LDA,
prepared from i-Pr2NH (0.71 mL, 5.0 mmol) and n-BuLi (2.2 mL, 5.5 mmol; 2.5 M in hexanes), in dry
THF (3.5 mL) at room temperature was added a suspension of 15b (2.5 g, 5.0 mmol) in DMSO (165 mL)
and the solution was stirred at room temperature for 1 h. Afterwards benzyl bromide (1.2 mL, 10 mmol)
was added and the solution was stirred at room temperature for 2 h. The reaction was quenched by
addition of brine (450 mL) and the mixture extracted with EtOAc (3 × 300 mL). The combined organic
extracts were washed with brine (2 × 250 mL), dried over Na2SO4 and concentrated under reduced
pressure. Purification of the residue by flash chromatography (pentane/EtOAc, 12:1) provided 16b (2.6 g,
1
88%) as a yellow oil. Rf = 0.37 (pentane/EtOAc, 10:1). H-NMR (300 MHz, CDCl3): δ = 0.88 (t,
J = 6.6 Hz, 3 H, 12´-H3), 1.08 (d, J = 7.2 Hz, 18 H, CH(CH3)2), 1.171.48 (m, 21 H, 3´-H2 to 11´-H2,
CH(CH3)2), 1.58 (m, 2 H, 2´-H2), 2.70 (s, 3 H, 2-CH3), 2.77 (t, J = 7.8 Hz, 2 H, 1´-H2), 5.05 (s, 2 H,
-CH2Ph), 7.25 (dd, J = 9.0, 2.4 Hz, 1 H, 7-H), 7.34 (d, J = 2.4 Hz, 1 H, 5-H), 7.367.56 (m, 5 H,
5 × Ph-H), 7.87 (d, J = 9.0 Hz, 1 H, 8-H) ppm. 13C-NMR (150 MHz, CDCl3): δ = 12.63 (CH(CH3)2),
14.11 (C-12´), 17.88 (CH(CH3)2), 22.67 (C-11´), 23.29 (2-CH3), 26.83, 29.33, 29.38, 29.59, 29.63, 29.64,
29.65, 29.97, 30.08, 31.90 (C-1´ to C-10´), 76.02 (-CH2Ph), 108.2 (C-5), 123.3 (C-3), 124.6 (C-7), 126.7
(C-4a), 127.3 (2  Ph-Co), 128.6 (2  Ph-Cm), 128.1, 130.1 (C-8, Ph-Cp), 136.9, 144.0 (C-8a, Ph-Ci),
153.6, 157.7, 158.5 (C-2, C-4, C-6) ppm. IR (film): ̃ = 2924, 2865, 1619, 1593, 1492, 1463, 1388, 1364,

HETEROCYCLES, Vol. 82, No. 1, 2010
389
1346, 1267, 1233, 1206, 1121, 1058, 997, 947, 882, 835, 732, 692 cm-1. UV (CH3CN): λmax (lg ) = 234.5
(4.751), 269.5 (3.653), 279.0 (3.664), 318.0 (3.484), 330.5 (3.559), 358.0 nm (2.385). MS (ESI): m/z (%)
= 590.4 (100) [M+H]+. HRMS (ESI): calcd. for C38H59NO2Si + H+ 590.4387; found 590.4387.
4-Benzyloxy-3-dodecyl-2-methylquinolin-6-ol (17b): TBAF·3 H2O (2.12 g, 6.71 mmol) was added to a
solution of 16b (1.98 g, 3.36 mmol) in THF (25 mL) at 0 °C. After stirring at 0 °C for 1 h and at room
temperature for 2 h the solution was concentrated under reduced pressure. Purification of the residue by
flash chromatography (CH2Cl2/MeOH, 97:3) provided 17b (1.43 g, 98%) as a pale-yellow solid. Rf = 0.38
(CH2Cl2/MeOH, 95:5). 1H-NMR (300 MHz, CDCl3): δ = 0.85 (t, J = 6.6 Hz, 3 H, 12´-H3), 1.121.41 (m,
18 H, 3´-H2 to 11´-H2), 1.49 (m, 2 H, 2´-H2), 2.602.78 (m, 5 H, 2-CH3, 1´-H2), 4.97 (s, 2 H, -CH2Ph),
7.19 (dd, J = 9.0, 2.4 Hz, 1 H, 7-H), 7.267.39 (m, 5 H, 5 × Ph-H), 7.42 (d, J = 2.4 Hz, 1 H, 5-H), 7.83 (d,
J = 9.0 Hz, 1 H, 8-H) ppm. 13C-NMR (75 MHz, CDCl3): δ = 14.12 (C-12´), 21.94 (2-CH3), 22.68 (C-11'),
26.66, 29.34, 29.59, 29.64, 29.91, 30.04, 31.90 (C-1´ to C-10´), 76.02 (-CH2Ph), 104.0, (C-5), 121.7 (C-7),
124.2, 127.2 (C-3, C-4a), 127.5 (2  Ph-Co), 128.2, 128.7 (C-8, Ph-Cp), 128.5 (2  Ph-Cm), 136.6, 142.0
(C-8a, Ph-Ci), 155.6, 156.5, 159.2 (C-2, C-4, C-6) ppm. IR (KBr): ̃ = 2956, 2922, 2851, 2555, 1873,
1620, 1592, 1517, 1469, 1393, 1357, 1267, 1241, 1207, 1123, 1084, 1057, 1015, 973, 909, 860, 846, 827,
747, 719, 698, 617, 541, 484 cm-1. UV (MeOH): λmax (lg ) = 200.5 (4.324), 232.5 (4.702), 282.5 (3.668),
335.0 nm (3.653). MS (ESI): m/z (%) = 434.3 (100) [M+H]+. HRMS (ESI): calcd. for C29H39NO2 + H+
434.3053; found 434.3053.
4-Benzyloxy-6-[2-(dimethylamino)ethoxy]-3-dodecyl-2-methylquinoline (18b): Sodium hydride
(0.302 g, 7.56 mmol, 60% in mineral oil) was added slowly to a solution of 17b (1.43 g, 3.29 mmol) in
DMF (25 mL) at 0 °C. After stirring for 1 h at room temperature, the solution was cooled to 0 °C,
2-dimethylaminoethyl chloride hydrochloride (0.497 g, 3.45 mmol) was added and the suspension was
stirred at 100 °C for 2 h. After cooling to room temperature the reaction was quenched by addition of H2O
(25 mL) and the mixture extracted with EtOAc (3 × 50 mL). The combined organic extracts were washed
with H2O (2 × 100 mL) and brine (100 mL), dried over Na2SO4 and concentrated under reduced pressure.
Purification of the residue by flash chromatography (CH2Cl2/MeOH, 96:4) provided 18b (0.916 g, 95%)
1
as an orange oil. Rf = 0.15 (CH2Cl2/MeOH, 98:2, 0.5% NEt3). H-NMR (300 MHz, CDCl3): δ = 0.85 (t,
J = 6.6 Hz, 3 H, 12´´-H3), 1.181.44 (m, 18 H, 3´´-H2 to 11´´-H2), 1.55 (m, 2 H, 2´´-H2), 2.33 (s, 6 H,
N(CH3)2), 2.68 (s, 3 H, 2´-CH3), 2.70–2.80 (m, 4 H, 1´´-H2, 1-H2), 4.01 (t, J = 6.0 Hz, 2 H, 2-H2), 5.04 (s,
2 H, -CH2Ph), 7.17 (d, J = 2.4 Hz, 1 H, 5´-H), 7.27 (dd, J = 9.0, 2.4 Hz, 1 H, 7´-H), 7.327.52 (m, 5 H,
13
5 × Ph-H), 7.86 (d, J = 9.0 Hz, 1 H, 8´-H) ppm. C-NMR (75 MHz, CDCl3): δ = 14.10 (C-12´´), 22.66
(C-11´´), 23.26 (2´-CH3), 26.84, 29.32, 29.37, 29.57, 29.61, 29.63, 29.90, 30.00, 31.89 (C-1´´ to C-10´´),

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45.85 (N(CH3)2), 58.16 (C-1), 66.05 (C-2), 76.18 (-CH2Ph), 100.6 (C-5´), 121.5 (C-7´), 123.2, 126.8
(C-3´, C-4a´), 127.5 (2  Ph-Co), 128.2, 130.1 (C-8, Ph-Cp), 128.6 (2  Ph-Cm), 137.1, 143.9 (C-8a´,
Ph-Ci), 156.3, 157.5, 158.9 (C-2´, C-4´, C-6´) ppm. IR (film): ̃ = 2924, 2853, 2770, 1622, 1593, 1495,
1456, 1349, 1269, 1226, 1121, 1030, 832, 734, 697 cm-1. UV (CH3CN): λmax (lg ) = 233.5 (4.787), 257.5
(3.672), 267.0 (3.714), 276.0 (3.704), 318.5 (3.591), 331.5 (3.673), 357.5 nm (2.260). MS (ESI): m/z (%)
= 505.3 (100) [M+H]+, 1009.7 (29) [2M+H]+. HRMS (ESI): calcd. for C33H48N2O2 + H+ 505.3788; found
505.3787.
4-Benzyloxy-6-[2-(dimethylamino)ethoxy]-3-dodecyl-2-methylquinoline N,N’-dioxide (19b):
A
solution of m-chloroperbenzoic acid (1.85 g, 7.52 mmol, 70%) in CH2Cl2 (160 mL) was added to a
solution of 18b (1.58 g, 3.13 mmol) in CH2Cl2 (160 mL). After stirring for 1.5 h at room temperature the
solution was washed with saturated aq. NaHCO3 (2 × 320 mL), dried over Na2SO4 and concentrated
under reduced pressure. Purification of the residue by flash chromatography (MeOH) provided 19b
1
(1.42 g, 80%) as a yellowish solid. Rf = 0.18 (MeOH). H-NMR (300 MHz, CDCl3): δ = 0.85 (t,
J = 6.6 Hz, 3 H, 12´´-H3), 1.151.40 (m, 18 H, 3´´-H2 to 11´´-H2), 1.52 (m, 2 H, 2´´-H2), 2.67 (s, 3 H,
2´-CH3), 2.73 (t, J = 8.4 Hz, 2 H, 1´´-H2), 3.28 (s, 6 H, N(CH3)2), 3.62 (t, J = 4.2 Hz, 2 H, 1-H2), 4.57 (t,
J = 4.2 Hz, 2 H, 2-H2), 5.04 (s, 2 H, -CH2Ph), 7.207.50 (m, 7 H, 5´-H, 7´-H, 5 × Ph-H), 8.65 (d,
J = 9.6 Hz, 1 H, 8´-H) ppm. 13C-NMR (125 MHz, CDCl3): δ = 14.08 (C-12´´), 15.17 (2´-CH3), 22.65,
27.29, 29.29, 29.30, 29.53, 29.59, 29.61, 29.72, 29.87, 31.88 (C-1´´ to C-11´´), 60.35 (N(CH3)2), 62.34
(C-2), 69.86 (C-1), 77.10 (-CH2Ph), 101.9 (C-5´), 121.4, 122.3 (C-7´, C-8´), 125.0 (C-3´), 127.8
(2  Ph-Co), 128.6 (Ph-Cp), 128.8 (2  Ph-Cm), 128.9 (C-4a´), 136.4, 136.8 (Ph-Ci, C-8a´), 145.7 (C-2´),
149.8 (C-4´), 156.8 (C-6´) ppm. IR (KBr): ̃
= 2919, 1621, 1573, 1454, 1324, 1237, 1123, 959, 697 cm-1.
UV (MeOH): λmax (lg ) = 243.5 (4.676), 323.0 nm (3.903). MS (ESI): m/z (%) = 537.37 (100) [M+H]+,
1073.73 (43) [2M+H]+. HRMS (ESI): calcd. for C33H48N2O4 + H+ 537.3683; found 537.3687.
6-[2-(Dimethylamino)ethoxy]-3-dodecyl-1-hydroxy-2-methyl-4-quinolone (4): Pd/C (10%, 130 mg)
was added to a solution of 19b (0.994 g, 1.85 mmol) in EtOH (150 mL). After applying an H2 atmosphere
(1 bar), the solution was stirred at room temperature for 1.5 h. After filtration through celite, which was
thoroughly rinsed with EtOH (200 mL), the filtrate was concentrated under reduced pressure and the
residue recrystallised from EtOH/acetone to give 4 (0.708 g, 89%) as a colorless solid. Rf = 0.42 (MeOH);
1
m.p. 144 °C. H-NMR (300 MHz, CDCl3): δ = 0.85 (t, J = 6.6 Hz, 3 H, 12´-H3), 1.101.40 (m, 20 H,
2´-H2 to 11´-H2), 2.32 (s, 6 H, N(CH3)2), 2.42 (s, 3 H, 2-CH3), 2.55 (t, J = 8.4 Hz, 2 H, 1´-H2), 2.72 (t,
J = 4.2 Hz, 2 H, 2´´-H2), 3.92 (t, J = 4.2 Hz, 2 H, 1´´-H2), 6.90 (d, J = 9.0 Hz, 1 H, 7-H), 7.44 (d,
J = 1.8 Hz, 1 H, 5-H), 8.65 (d, J = 9.0 Hz, 1 H, 8-H), 10.8 (sbr, 1 H, 1-OH) ppm. 13C-NMR

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(125 MHz, CDCl3): δ = 14.07 (C-12´), 14.62 (2-CH3), 22.64 (C-11´), 26.53 (C-1´), 29.33, 29.63, 29.70,
29.94 (C-2´ to C-9´), 31.88 (C-10´), 45.50 (N(CH3)2), 57.86 (C-2´´), 65.39 (C-1´´), 104.4 (C-5), 117.4
(C-8), 119.7 (C-3), 122.3 (C-7), 124.6 (C-4a), 134.8 (C-8a), 147.5 (C-2), 155.1 (C-6), 170.1 (C-4) ppm.
IR (KBr): ̃
= 2921, 2850, 1540, 1467, 1035 cm-1. UV (MeOH): λmax (lg ) = 202.0 (4.125), 221.0 (4.457),
242.5 (4.363), 261.5 (4.355), 270.5 (4.220), 347.0 (3.873), 357.5 nm (3.872). MS (ESI): m/z (%) = 431.33
(100) [M+H]+, 861.64 (100) [2M+H]+. HRMS (ESI): calcd. for C26H42N2O3 + H+ 431.3269; found
431.3268.
Synthesis of 6-[2-(dimethylamino)ethoxy]-2-dodecyl-1-hydroxy-4-quinolone (5)
Ethyl 3-[4-(triisopropylsilyloxy)phenylamino]-2-pentadecenoate (14c): Ester 10c (7.11 g, 25.0 mmol),
molecular sieves 3 Å (5.00 g) and acetic acid (0.30 mL) were added to a solution of 13 (10.6 g,
40.0 mmol) in EtOH (150 mL). After stirring for 44 h at 75 °C the precipitate was separated by filtration
through celite, which was thoroughly rinsed with EtOH (150 mL), and the filtrate was concentrated under
reduced pressure. Purification of the residue by flash chromatography (pentane/EtOAc, 20:1) provided
1
14c (11.9 g, 89%) as a brown oil. Rf = 0.46 (pentane/EtOAc, 20:1). H-NMR (300 MHz, CDCl3): δ =
0.88 (t, J = 6.6 Hz, 3 H, 15-H3), 1.09 (d, J = 6.6 Hz, 18 H, CH(CH3)2), 1.121.43 (m, 26 H, 5-H2 to 14-H2,
CH(CH3)2, OCH2CH3), 2.17 (t, J = 7.2 Hz, 2 H, 4-H2), 4.14 (q, J = 6.6 Hz, 2 H, OCH2CH3), 4.65 (s, 1 H,
2-H), 6.83 (d, J = 8.4 Hz, 2 H, 2´-H, 6´-H), 6.95 (d, J = 8.4 Hz, 2 H, 3´-H, 5´-H), 10.09 (sbr, 1 H,
13
NH) ppm. C-NMR (150 MHz, CDCl3): δ = 12.58 (CH(CH3)2), 14.10, 14.61 (OCH2CH3, C-15), 17.85
(CH(CH3)2), 22.68 (C-14), 27.98, 29.15, 29.18, 29.33, 29.40, 29.55, 29.61, 29.63, 31.90, 32.30 (C-4 to
C-13), 58.60 (OCH2CH3), 83.64 (C-2), 120.2 (C-2´, C-6´), 127.2 (C-3´, C-5´), 132.3 (C-1´), 154.0 (C-4´),
164.6 (C-3), 170.7 (C-1) ppm. IR (film): ̃ = 3246, 2926, 2866, 1655, 1611, 1511, 1465, 1384, 1255,
1159, 1096, 1049, 1013, 996, 913, 883, 845, 788, 685 cm-1. UV (CH3CN): λmax (lg ) = 294.5 nm (4.369).
MS (ESI): m/z (%) = 532.4 (100) [M+H]+. HRMS (ESI): calcd. for C32H57NO3Si + H+ 532.4180; found
532.4178.
2-Dodecyl-6-triisopropylsilyloxy-4-quinolone (15c): Ester 14c (11.5 g, 21.6 mmol) was added dropwise
to refluxing diphenyl ether (110 g) and the formed EtOH was removed by distillation. After stirring for
1 h at 260 °C and cooling to room temperature, diphenyl ether was evaporated under reduced pressure
(20 mbar, 80 °C) to afford the crude product which was absorbed on silica gel. Elution with CH2Cl2
(3.5 L) allowed to remove the remaining diphenyl ether and afterwards elution with EtOAc (1.5 L)
provided the product, which was recrystallised from EtOH/acetone to give 15c (8.31 g, 79%) as colorless
1
needles. Rf = 0.34 (CH2Cl2/MeOH, 95:5). H-NMR (300 MHz, CDCl3): δ = 0.84 (t, J = 6.6 Hz, 3 H,

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12´-H3), 0.99 (d, J = 7.2 Hz, 18 H, CH(CH3)2), 1.081.34 (m, 21 H, 3´-H2 to 11´-H2, CH(CH3)2), 1.70 (m,
2 H, 2´-H2), 2.66 (t, J = 7.2 Hz, 2 H, 1´-H2), 6.18 (s, 1 H, 3-H), 7.14 (dd, J = 9.0, 2.4 Hz, 1 H, 7-H),
7.687.75 (m, 2 H, 5-H, 8-H), 12.81 (sbr, 1 H, NH) ppm. 13C-NMR (75 MHz, CDCl3): δ = 12.59
(CH(CH3)2), 14.09 (C-12´), 17.83 (CH(CH3)2), 22.67 (C-11´), 29.15, 29.32, 29.35, 29.40, 29.55, 29.64,
29.67, 31.90, 34.24 (C-1´ to C-10´), 107.0 (C-3), 112.4 (C-8), 120.1 (C-5), 126.0 (C-4a), 126.1 (C-7),
135.6 (C-8a), 152.4, 154.4 (C-2, C-6), 178.0 (C-4) ppm. IR (KBr): ̃ = 3061, 2922, 2850, 1637, 1589,
1546, 1495, 1371, 1301, 1263, 1222, 1174, 1135, 1080, 995, 961, 882, 842, 809, 685, 621, 579, 509 cm-1.
UV (MeOH): λmax (lg ) = 215.5 (4.373), 242.0 (4.599), 284.0 (3.600), 295.5 (3.596), 330.0 (3.946),
342.5 nm (3.902). MS (ESI): m/z (%) = 486.3 (100) [M+H]+, 971.7 (86) [2M+H]+, 1457.1 (19) [3M+H]+.
HRMS (ESI): calcd. for C30H51NO2Si + H+ 486.3761; found 486.3763.
4-Benzyloxy-2-dodecyl-6-(triisopropylsilyloxy)quinoline (16c): To a solution of LDA, prepared from
i-Pr2NH (0.44 mL, 3.1 mmol) and n-BuLi (1.4 mL, 3.4 mmol; 2.5 M in hexanes), in dry THF (2 mL) at
room temperature was added a suspension of 15c (1.5 g, 3.1 mmol) in DMSO (100 mL) and the solution
was stirred at room temperature for 1.25 h. Afterwards benzyl bromide (0.73 mL, 6.2 mmol) was added
and the solution was stirred at room temperature for 45 min. The reaction was quenched by addition of
brine (300 mL) and the mixture extracted with EtOAc (3 × 200 mL). The combined organic extracts were
washed with brine (3 × 200 mL), dried over Na2SO4 and concentrated under reduced pressure.
Purification of the residue by flash chromatography (pentane/EtOAc, 15:1  8:1) provided 16c (1.3 g,
1
71%) as a yellow oil. Rf = 0.42 (pentane/EtOAc, 10:1). H-NMR (300 MHz, CDCl3): δ = 0.88 (t,
J = 6.6 Hz, 3 H, 12´-H3), 1.12 (d, J = 7.2 Hz, 18 H, CH(CH3)2), 1.201.44 (m, 21 H, 3´-H2 to 11´-H2,
CH(CH3)2), 1.76 (m, 2 H, 2´-H2), 2.86 (t, J = 7.2 Hz, 2 H, 1´-H2), 5.27 (s, 2 H, -CH2Ph), 6.65 (s, 1 H,
3-H), 7.29 (dd, J = 9.0, 2.4 Hz, 1 H, 7-H), 7.357.52 (m, 5 H, 5 × Ph-H), 7.60 (d, J = 2.4 Hz, 1 H, 5-H),
13
7.86 (d, J = 9.0 Hz, 1 H, 8-H) ppm. C-NMR (75 MHz, CDCl3): δ = 12.62 (CH(CH3)2), 14.12 (C-12´),
17.93 (CH(CH3)2), 22.68 (C-11´), 29.36, 29.57, 29.61, 29.64, 29.65, 29.67, 30.24, 31.91, 39.80 (C-1´ to
C-10´), 69.75 (-CH2Ph), 100.9 (C-3), 108.5 (C-5), 120.8 (C-4a), 125.1 (C-7), 127.0 (2  Ph-Co), 128.1,
129.6 (C-8, Ph-Cp), 128.6 (2  Ph-Cm), 136.2, 144.6 (C-8a, Ph-Ci), 153.1 (C-6), 160.3, 161.7 (C-2,
C-4) ppm. IR (film): ̃ = 3066, 2924, 2865, 1598, 1564, 1498, 1470, 1404, 1357, 1266, 1216, 1179, 1095,
996, 959, 882, 837, 801, 734, 693 cm-1. UV (MeOH): λmax (lg ) = 235.0 (4.792), 269.5 (3.746), 277.5
(3.829), 287.0 (3.734), 317.0 (3.526), 328.5 nm (3.548). MS (ESI): m/z (%) = 576.4 (100) [M+H]+.
HRMS (ESI): calcd. for C37H57NO2Si + H+ 576.4231; found 576.4233.
4-Benzyloxy-2-dodecylquinolin-6-ol (17c): TBAF·3 H2O (2.16 g, 6.84 mmol) was added to a solution of
16c (1.97 g, 3.42 mmol) in THF (20 mL) at 0 °C. After stirring at 0 °C for 1 h and at room temperature

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for 3.5 h the solution was concentrated under reduced pressure. Purification of the residue by flash
chromatography (pentane/EtOAc, 4:1) provided 17c (1.30 g, 90%) as a colorless solid. Rf = 0.22
1
(pentane/EtOAc, 4:1). H-NMR (300 MHz, CDCl3): δ = 0.85 (t, J = 6.6 Hz, 3 H, 12´-H3), 1.051.35 (m,
18 H, 3´-H2 to 11´-H2), 1.68 (m, 2 H, 2´-H2), 2.86 (t, J = 7.8 Hz, 2 H, 1´-H2), 5.23 (s, 2 H, -CH2Ph), 6.63
(s, 1 H, 3-H), 7.18 (dd, J = 9.0, 2.4 Hz, 1 H, 7-H), 7.287.48 (m, 5 H, 5 × Ph-H), 7.62 (d, J = 2.4 Hz, 1 H,
13
5-H), 7.71 (d, J = 9.0 Hz, 1 H, 8-H), 12.08 (sbr, 1 H, OH) ppm. C-NMR (75 MHz, CDCl3): δ = 14.12
(C-12´), 22.67 (C-11´), 29.32, 29.36, 29.41, 29.46, 29.60, 30.32, 31.90, 38.50 (C-1´ to C-10´), 69.95
(-CH2Ph), 100.9, 104.6 (C-3, C-5), 121.6 (C-4a), 122.1 (C-7), 127.1 (2  Ph-Co), 127.8, 128.1 (C-8,
Ph-Cp), 128.6 (2  Ph-Cm), 135.8, 142.2 (C-8a, Ph-Ci), 155.4, 160.7, 161.0 (C-2, C-4, C-6) ppm. IR
(KBr): ̃ = 2921, 2850, 1620, 1591, 1531, 1466, 1390, 1351, 1323, 1268, 1220, 1184, 1163, 1096, 998,
834, 738, 696, 630, 604, 560, 472 cm-1. UV (MeOH): λmax (lg ) = 234.0 (4.730), 277.5 (3.806), 287.0
(3.709), 322.5 (3.604), 332.5 nm (4.618). MS (ESI): m/z (%) = 420.2 (100) [M+H]+. HRMS (ESI): calcd.
for C28H37NO2 + H+ 420.2897; found 420.2897.
4-Benzyloxy-6-[2-(dimethylamino)ethoxy]-2-dodecylquinoline (18c): Sodium hydride (0.109 g,
2.74 mmol, 60% in mineral oil) was added slowly to a solution of 17c (0.499 g, 1.19 mmol) in DMF
(6 mL) at 0 °C. After stirring for 1 h at room temperature the solution was cooled to 0 °C,
2-dimethylaminoethyl chloride hydrochloride (0.180 g, 1.25 mmol) was added and the suspension was
stirred at 100 °C for 2 h. After cooling to room temperature the reaction was quenched by addition of H2O
(10 mL) and the mixture extracted with EtOAc (3 × 20 mL). The combined organic extracts were washed
with H2O (2 × 50 mL) and brine (50 mL), dried over Na2SO4 and concentrated under reduced pressure.
Purification of the residue by flash chromatography (CH2Cl2/MeOH, 30:1, 1% NEt3) provided 18c
1
(0.572 g, 98%) as a colorless solid. Rf = 0.30 (CH2Cl2/MeOH, 30:1, 1% NEt3). H-NMR
(300 MHz, CDCl3): δ = 0.88 (t, J = 6.6 Hz, 3 H, 12´´-H3), 1.181.42 (m, 18 H, 3´´-H2 to 11´´-H2), 1.77
(m, 2 H, 2´´-H2), 2.38 (s, 6 H, N(CH3)2), 2.79 (t, J = 6.0 Hz, 2 H, 1-H2), 2.86 (t, J = 7.8 Hz, 2 H, 1´´-H2),
4.18 (t, J = 6.0 Hz, 2 H, 2-H2), 5.27 (s, 2 H, -CH2Ph), 6.67 (s, 1 H, 3´-H), 7.307.53 (m, 7 H, 5´-H, 7´-H,
13
5 × Ph-H), 7.89 (d, J = 9.0 Hz, 1 H, 8´-H) ppm. C-NMR (150 MHz, CDCl3): δ = 14.08 (C-12´´), 22.63
(C-11´´), 29.31, 29.51, 29.60, 29.62, 30.15, 31.86, 39.65 (C-1´´ to C-10´´), 45.84 (N(CH3)2), 58.17 (C-1),
66.12 (C-2), 70.05 (-CH2Ph), 100.8, 101.1 (C-3´, C-5´), 120.5 (C-4a´), 121.9 (C-7´), 127.4 (2  Ph-Co),
128.2, 129.7 (C-8´, Ph-Cp), 128.6 (2  Ph-Cm), 135.9, 144.6 (C-8a´, Ph-Ci), 155.9, 160.3, 161.5 (C-2´,
C-4´, C-6´) ppm. IR (KBr): ̃ = 2920, 2850, 2769, 1598, 1568, 1503, 1468, 1359, 1266, 1222, 1077, 1032,
991, 838, 732, 697 cm-1. UV (CH3CN): λmax (lg ) = 235.0 (4.737), 273.5 (3.801), 317.5 (3.484),
330.0 nm (3.528). MS (ESI): m/z (%) = 491.3 (28) [M+H]+, 401.3 (100) [MCH2Ph+H]+. HRMS (ESI):

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HETEROCYCLES, Vol. 82, No. 1, 2010
calcd. for C32H46N2O2 + H+ 491.3632; found 491.3631.
4-Benzyloxy-6-[2-(dimethylamino)ethoxy]-2-dodecylquinoline N,N’-dioxide (19c): A solution of
m-chloroperbenzoic acid (1.15 g, 4.68 mmol, 70%) in CH2Cl2 (100 mL) was added to a solution of 18c
(0.957 g, 1.95 mmol) in CH2Cl2 (100 mL). After stirring for 1.5 h at room temperature the solution was
washed with saturated aq. NaHCO3 (2 × 180 mL), dried over Na2SO4 and concentrated under reduced
pressure. Purification of the residue by flash chromatography (MeOH) provided 19c (0.857 g, 84%) as a
1
colorless solid. Rf = 0.17 (MeOH). H-NMR (300 MHz, CDCl3): δ = 0.85 (t, J = 6.6 Hz, 3 H, 12´´-H3),
1.201.50 (m, 18 H, 3´´-H2 to 11´´-H2), 1.78 (m, 2 H, 2´´-H2), 3.08 (t, J = 8.4 Hz, 2 H, 1´´-H2), 3.34 (s,
6 H, N(CH3)2), 3.72 (t, J = 4.2 Hz, 2 H, 1-H2), 4.72 (t, J = 4.2 Hz, 2 H, 2-H2), 5.27 (s, 2 H, -CH2Ph), 6.65
(s, 1 H, 3´-H), 7.307.50 (m, 6 H, 7´-H, 5 × Ph-H), 7.57 (d, J = 2.4 Hz, 1 H, 5´-H), 8.70 (d, J = 9.6 Hz,
1 H, 8´-H) ppm. 13C-NMR (125 MHz, CDCl3): δ = 14.08 (C-12´´), 22.65, 26.37, 29.32, 29.43, 29.53,
29.57, 29.61, 29.64, 31.83, 31.89 (C-1´´ to C-11´´), 60.32 (N(CH3)2), 62.55 (C-2), 69.98 (C-1), 70.91
(-CH2Ph), 102.1, 102.5 (C-5´, C-3´), 122.0, 122.2 (C-7´, C-8´), 122.7 (C-4a´), 127.6 (2  Ph-Co), 128.7
(Ph-Cp), 128.9 (2  Ph-Cm), 135.2, 137.5 (Ph-Ci, C-8a´), 148.0, 151.6 (C-2´, C-4´), 156.5 (C-6´) ppm. IR
(KBr): ̃
= 2921, 1576, 1471, 1202, 729 cm-1. UV (MeOH): λmax (lg ) = 201.0 (4.263), 233.0 (4.622),
264.5 (4.060), 320.5 nm (3.832). MS (ESI): m/z (%) = 523.35 (100) [M+H]+, 1045.70 (23) [2M+H]+.
HRMS (ESI): calcd. for C32H46N2O4 + H+ 523.3530; found 523.3533.
6-[2-(Dimethylamino)ethoxy]-2-dodecyl-1-hydroxy-4-quinolone (5): Pd/C (10%, 115 mg) was added to
a solution of 19c (0.857 g, 1.64 mmol) in EtOH (130 mL). After applying an H2 atmosphere (1 bar), the
solution was stirred at room temperature for 1.3 h. After filtration through celite, which was thoroughly
rinsed with EtOH (150 mL), the filtrate was concentrated under reduced pressure and the residue
recrystallised from EtOH/acetone to give 5 (0.499 g, 73%) as a colorless solid. Rf = 0.42 (MeOH); m.p.
152 °C. 1H-NMR (300 MHz, CDCl3): δ = 0.85 (t, J = 6.6 Hz, 3 H, 12´-H3), 1.081.30 (m, 18 H, 3´-H2 to
11´-H2), 1.47 (m, 2 H, 2´-H2), 2.34 (s, 6 H, N(CH3)2), 2.55 (m, 2 H, 1´-H2), 2.77 (t, J = 4.2 Hz, 2 H,
2´´-H2), 4.13 (t, J = 4.2 Hz, 2 H, 1´´-H2), 6.21 (s, 1 H, 3-H), 7.20 (dd, J = 9.0, 1.8 Hz, 1 H, 7-H), 7.56 (d,
J = 1.8 Hz, 1 H, 5-H), 7.98 (d, J = 9.0 Hz, 1 H, 8-H), 11.9 (sbr, 1 H, 1-OH) ppm. 13C-NMR
(125 MHz, CDCl3): δ = 14.07 (C-12´), 22.64 (C-11´), 27.43 (C-2´), 29.32, 29.34, 29.48, 29.59, 29.64,
29.69 (C-3´ to C-9´), 31.32 (C-1´), 31.89 (C-10´), 45.68 (N(CH3)2), 58.03 (C-2´´), 66.04 (C-1´´), 103.9
(C-5), 105.2 (C-3), 118.5 (C-8), 123.7 (C-7), 124.9 (C-4a), 136.0 (C-8a), 152.9 (C-2), 156.2 (C-6), 168.6
(C-4) ppm. IR (KBr): ̃
= 2922, 2854, 1467, 1234, 1028 cm-1. UV (MeOH): λmax (lg ) = 222.5 (4.557),
259.0 (4.206), 270.0 (4.240), 352.5 nm (3.893). MS (ESI): m/z (%) = 417.31 (22) [M+H]+, 833.61 (100)
[2M+H]+, 1249.92 (8) [3M+H]+. HRMS (ESI): calcd. for C25H40N2O3 + H+ 417.3112; found 417.3111.

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C25H40N2O3 (416.60): calcd. C 72.08 H 9.68; found C 71.87 H 9.90.
ACKNOWLEDGEMENTS
We thank the “Fonds der Chemischen Industrie” for financial support.
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