New 6-ethoxyquinolines as simple optoquine analogues

Article abstract of DOI:10.1081/SCC-120013738

Reaction of 6-ethoxylepidine (6-ethoxy-4-methylquinoline) with strong base and electrophiles leads to new derivatives, as possible optoquine analogues.

Full text of DOI:10.1081/SCC-120013738

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NEW 6-ETHOXYQUINOLINES AS SIMPLE OPTOQUINE
ANALOGUES
Raymond C. F. Jones a , Russell J. Collighan b , Joanna Crane b , Nikolas J. Hodges b ,
Matthew S. Ling b & Joanne Stroud b
a Department of Chemistry , Loughborough University , Loughborough, Leics, LE11 3TU, UK
b Department of Chemistry , Nottingham University , Nottingham, NG7 2RD, UK
Published online: 16 Aug 2006.
To cite this article: Raymond C. F. Jones , Russell J. Collighan , Joanna Crane , Nikolas J. Hodges , Matthew S. Ling & Joanne
Stroud (2002) NEW 6-ETHOXYQUINOLINES AS SIMPLE OPTOQUINE ANALOGUES, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 32:20, 3185-3191, DOI: 10.1081/SCC-120013738
To link to this article: http://dx.doi.org/10.1081/SCC-120013738
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SYNTHETIC COMMUNICATIONS
Vol. 32, No. 20, pp. 3185–3191, 2002
NEW 6-ETHOXYQUINOLINES AS
SIMPLE OPTOQUINE ANALOGUES
*
Raymond C. F. Jones, Russell J. Collighan,
Joanna Crane, NikolasJ. Hodge,s
Matthew S. Ling, and Joanne Stroud
Department of Chemistry, Nottingham University,
Nottingham NG7 2RD, UK
ABSTRACT
Reaction of 6-ethoxylepidine (6-ethoxy-4-methylquinoline)
with strong base and electrophiles leads to new derivatives,
as possible optoquine analogues.
Key Words: Optoquine; 6-Ethoxyquinolines; 6-Ethoxylepi-
dine
The pneumococcus is a major pathogen of man, responsible for as
many as 30,000 deaths per annum from a variety of diseases including
pneumonia, bacterial meningitis, septic arthritis andsepticaemia. The sen-
sitivity of pneumococcus to optoquine 1 is usedto differentiate pneumococ-
cus from low grade pathogens. Although effective antibiotic treatments
for pneumococcal infections exist, there is interest in the role of optoquine
*Corresponding author. Current address: Department of Chemistry, Loughborough
University, Loughborough, Leics, LE11 3TU, UK. Fax: þ44 1509 223926; E-mail:
r.c.f.jones@lboro.ac.uk
3185
DOI: 10.1081/SCC-120013738
Copyright & 2002 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
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3186
JONES ET AL.
[1]
in vivo, andas a new leadto an antipneumococcal drugs.
Promptedby
the scant attention paidin the literature to 6-ethoxyquinolines, we report
here our studies on much simplified structures related to the quinoline
portion of optoquine andin particular to 6-ethoxylepidine (6-ethoxy-4-
methylquinoline; 2), which has been foundto retain some (approx. 1%)
of the biological activity of optoquine 1.[2]
6-Ethoxylepidine 2 was preparedin low isolatedyield(13%) but on a
multigram scale, after an extensive purification sequence, from 4-ethoxyani-
line andbut-3-en-2-one using a proceudre reportedfor the 6-methoxy
analogue (FeCl3, ZnCl2, conc. HCl, EtOH).[3]
Our strategy was to modify the C(4)-methyl group of 2, including
elaboration to incorporate a heteroatom, by utilising its potential for depro-
tonation to anion 3.[4] Thus treatment of 6-ethoxylepidine 2 with lithium
diisopropylamide followed by an electrophile (THF, ꢀ 78!20ꢁC) afforded
the new derivatives 4a–f after reaction with iodoethane, ethanal, propanone,
benzaldehyde, 2-naphthaldehyde and pyridine-2-aldehyde, respectively
Scheme 1. Reagents: i, LDA, THF, ꢀ 78ꢁC; ii, electrophile (EtI, MeCHO, Me2CO,
PhCHO, 2-naphthaldehyde, or pyridine-2-aldehyde), ꢀ78 ! 208C.

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6-ETHOXYQUINOLINES
3187
(Sch. 1). Quantities of starting material 2 were detected in the crude
reaction products, and it is possible that some of the carbonyl additions
are reversible, with adducts reverting on warming to room temperature
before quenching. Attemptedalkylations with
N-bromomethyl- and
N-(3-bromopropyl)phthalimide, and additions to 3-quinuclidone and to the
imine benzylidene aniline, did not afford products under these conditions.
Acylation with ethyl chloroformate ledto isolation of the N,C-diacylated
material 5 along with recoveredstarting material 2.
In addition to compounds 4a–f, we also preparedthree new 6-ethoxy-
quinolones. The 4-quinolone 6a was accessedby pyrolysis of the enamino-
ester formedfrom 4-ethoxyaniline andmethoxymethylene Melrdum’s
[6]
acid;[5] both solution[5] andflash vacuum methosd
were successful.
The 2-methyl-4-quinolone 6b and4-methyl-2-quinolone 7 were prepared
by treatment of 4-ethoxyaniline with ethyl acetoacetate (20ꢁC, 48 h, or
120–140ꢁC, 30 min, respectively) followedby aciidc cyclisation.
4-quinolones have a C(4)-hetero substituent andthe C(4) methyl group in
[7]
The
7 has potential for elaboration.
All of the above compounds were subjected to preliminary screening
for anti-pneumococcal activity; increasedactivity over that of 6-ethoxyl-
epidine 2 was indicated by the 4-(2-phenyl-2-hydroxyethyl) adduct 3d,
which hadactivity at 12% of that of optoquine.
EXPERIMENTAL
Melting points (uncorrected) was determined on a Gallenkamp
capillary apparatus. IR spectra were recorded on a Perkin-Elmer 1600
series FTIR spectrometer, mass spectra using a VG70E spectrometer, and
1H NMR spectra using a Bruker WM 250 instrument at 250 MHz unless
otherwise stated. Column chromatography was carried out under medium
pressure using Merck Kieselgel 60 silica gel (Art. 7729), andTLC using silica
plates, Camlab SilG/UV254. Organic solutions were dried with MgSO4.

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3188
JONES ET AL.
6-Ethoxy-4-methylquinoline 2: 4-Ethoxyaniline (79.9 g, 0.58 mol),
iron(III) chloride hexahydrate (251.9 g, 0.93 mol), anhydrous zinc chloride
(10.0 g), ethanol (450 cm3) andconc. hydrochloric acid(57 cm 3) were heated
together to 60–65ꢁC with stirring before the dropwise addition over 1 h of
but-3-en-2-one (38.8 cm3, 32.6 g, 0.46 mol). The mixture was then heated
at reflux for 3 h, left to standovernight, andthe ethanol removedunder
reduced pressure. The residue was basified with aqueous sodium hydroxide
(25% w/v) andthe mixture filteredthrough kieselguhr, to remove black
tarry solids, and extracted with ether. The ether extracts, combined with
the ether solution obtainedby repeatedwashing of the black solids, were
dried, filtered and evaporated under reduced pressure. The residual
brown oil was distilled under reduced pressure, collecting the fraction b.p.
90–120ꢁC at 1.5 mm Hg as an oil which solidified to a yellow–white solid.
Final purification by kugelrohr distillation afforded the tiꢁtle compound 2
as an off-white crystalline solid(11.2 g, 13%), m.p. 62–65 C (Found: Mþ
187.098. C12H13NO requires: M 187.100); ꢀmax: (CHCl3)/cmꢀ1 3260, 2942,
1622, 1596, 1363; ꢁ(CHCl3) 1.50 (3H, t, J 7 Hz, CH3CH2O), 2.64 (3H, s,
4-CH3), 4.17 (2H, q, J 7 Hz, CH3CH2O), 7.20 (2H, m, 3-H, 5-H), 7.60 (1H,
dd, J 2.5, 9 Hz, 7-H), 8.00 (1H, d, J 9 Hz, 8-H), 8.62 (1H, d, J 4 Hz, 2-H);
m/z 187 (Mþ).
General method for preparation of 4-substituted 6-ethoxyquinolines
4a–f: To 6-ethoxy-4-methylquinoline 2 (0.5 g, 2.7 mmol) in dry THF (20 cm3)
at ꢀ 78ꢁC under nitrogen was added lithium diisopropylamide (4 mmol, as a
solution in THF–hexanes). The mixture was stirredat ꢀ 78ꢁC for 30 min
before addition of the electrophile (3 mmol). After stirring for a further
15 min, the mixture was allowedto warm to room temperature, poured
3
into saturatedbrine (20 cm ) andextractedwith diethyl ether (2 ꢂ 25 cm3).
The ethereal extracts were dried, the solvents removed under reduced pres-
sure, andthe residue was purifiedby column chromatography, eluting
with chloroform : methanol (99 : 1 v/v) or ethyl acetate : hexane : triethylamine
(40 : 55 : 5 v/v/v) to affordthe title compounds. When ethyl chloroformate
was usedas electrophile (with R. VIPOND), a compoundwas isolated
in low yieldthat was assignedas the N,C-diacylated material 5 from its
1H NMR spectrum, which displayed signals for three ethoxy groups
along with the remainder of the expected pattern.
6-Ethoxy-4-propylquinoline 4a: Preparedusing iodoethane as electro-
phile, as a waxy white solid(41%) (Found: M þ 215.131. C14H17NO requires
M 215.131); ꢀmax (CHCl3)/cmꢀ1 3196, 2934, 2824, 1698, 1621, 1592, 1462,
1316; ꢁ (CHCl3) 1.04 (3H, t, J 8 Hz, CH3CH2CH2), 1.49 (3H, t, J 7 Hz,
CH3CH2O), 1.75 (2H, m, CH3CH2CH2), 2.95 (2H, m, CH3CH2CH2), 4.10
(2H, q, J 7 Hz, CH3CH2O), 7.40 (3H, m, ArH), 8.20 (1H, d, J 8 Hz, 8-H),
8.80 (1H, d, J 4 Hz, 2-H); m/z 215 (Mþ), 187, 172, 170, 159, 128.

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6-ETHOXYQUINOLINES
3189
6-Ethoxy-4-(2-hydroxypropyl)quinoline 4b: Preparedusing ethanal as
electrophile, as a waxy white solid(27%) (Found: M þ 231.126. C14H17NO2
requires
M
231.126); ꢀmax (CHCl3)/cmꢀ1 3314, 2933, 1621, 1592,
1403; ꢁ (CHCl3) 1.42 (3H, d, J 7 Hz, CH3CH), 1.50 (3H, t, J 7 Hz,
CH3CH2O), 2.45 (1H, br, s, OH), 3.40 (2H, d, J 8 Hz, CH2CH), 4.20 (3H,
m, CH3CH2O, CHOH), 7.3 (3H, m, ArH), 8.05 (1H, d, J 8 Hz, 8-H), 8.60
(1H, d, J 4 Hz, 2-H); m/z 231 (Mþ), 198, 187, 180, 172, 127.
6-Ethoxy-4-(2-hydroxy-2-methylpropyl)quinoline 4c: Preparedusing
propanone as electrophile, as a waxy white solid(38%) (Foun:d Mþ
245.143, C15H19NO2 requires M 245.142); ꢀmax (CHCl3)/cmꢀ1 3285, 2943,
1621, 1593; ꢁ (CHCl3) 1.32 (6H, s, 2 ꢂ CH3C), 1.48 (3H, t, J 7 Hz,
CH3CH2O), 1.73 (1H, br, s, OH), 3.22 (2H, s, CH2C), 4.17 (2H, q, J
7 Hz, CH3CH2O), 7.30 (3H, m, ArH), 8.04 (1H, d, J 8 Hz, 8-H), 8.06 (1H,
d, J 4 Hz, 2-H); m/z 245 (Mþ), 213, 201, 187, 172.
6-Ethoxy-4-(2-hydroxy-2-phenylethyl)quinoline 4d: Preparedusing
benzaldehyde as electrophile, as a white solid, m.p. 138–140ꢁC (56%)
(Found: C, 77.58; H, 6.66; N, 4.71%. C19H19NO2 requires: C, 77.79; H,
6.53; N, 4.77%); ꢀmax (CHCl3)/cmꢀ1 3447, 1621, 1463; ꢁ (CHCl3) 1.47 (3H,
t, J 7 Hz, CH3CH2O), 2.44 (1H, br, s, OH), 3.40 (2H, d, J 8 Hz, CH2CH),
4.10 (2H, q, J 7 Hz, CH3CH2O), 5.10 (1H, t, J 8 Hz, CHOH), 7.15–7.40
(8H, m, ArH), 7.90 (1H, d, J 9 Hz, 8-H), 8.30 (1H, d, J 4.5 Hz, 2-H);
m/z 293 (Mþ), 187, 172, 158.
6-Ethoxy-4-[2-hydroxy-2-(2-naphthyl)ethyl]quinoline 4e: Prepared
using 2-naphthaldehyde as electrophile (26%) (Found C, 80.58; H, 6.22;
N, 4.29%. C23H21NO2 requires: C, 80.44; H, 6.16; N, 4.08%); ꢁ (CHCl3)
1.43 (3H, t, J 7 Hz, CH3CH2O), 3.78 and 3.90 (each 1H, dd, J 2.5 and8 Hz,
CH2CH), 4.05 (2H, q, J 7 Hz, CH3CH2O), 5.45 (1H, t, J 8 Hz, CHOH),
7.30–7.80 (10H, m, ArH), 8.10 (1H, d, J 9 Hz, 8-H), 8.60 (1H, d, J 5.5 Hz,
2-H), 11.05 (1H, br, s, OH).
6-Ethoxy-4-[2-hydroxy-2-(2-pyridyl)ethyl]quinoline 4f: Preparedusing
pyridine-2-aldehyde as electrophile (10%) (Found C, 73.16; H, 6.26; N,
9.71%. C18H18N2O2 requires: C, 73.45; H, 6.16; N, 9.52%); ꢁ (CHCl3)
1.50 (3H, t, J 7 Hz, CH3CH2O), 3.52 (2H, d, J 8 Hz, CH2CH), 4.22
(3H, m, CH3CH2O, OH), 5.18 (1H, t, J 8 Hz, CHOH), 7.0–7.7 (7H,
m, ArH), 8.05 (1H, d, J 9.5 Hz, 8-H), 8.6 (1H, d, J 5 Hz, 2-H), 11.05 (1H,
s, OH).
6-Ethoxy-4-quinolone 6a: (in part with J. JENKIN andM. E.
JOHNSON) To methoxymethylene Meldrum’s acid[5] (5.00 g, 0.027 mol)
in dry acetonitrile (50 cm3) was added freshly distilled 4-ethoxyaniline
(3.83 g, 0.028 mol) andthe mixture heatedunder reflux for 8 h before cooling
to 0ꢁC. The bright yellow solidwas collectedby filtration, washing with cold
methanol, to afford (4-ethoxyphenyl)aminomethylene Meldrum’s acid, m.p.

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3190
JONES ET AL.
155–156ꢁC (7.27 g, 92%) (Found: C, 61.76; H, 6.01; N, 5.07%. C19H17N3O
requires: C, 61.85; H, 5.88; N, 4.81%); ꢀmax (CHCl3)/cmꢀ1 3186, 2927, 1721,
1681, 1625, 1519, 1587 and1459; ꢁ (CDCl3) 1.43 (3H, t, J 7 Hz, CH3CH2O),
1.75 (6H, s, 2 ꢂ CH3), 4.04 (2H, q, J 7 Hz, CH3CH2O), 6.93 and7.17 (each
2H, d, J 9 Hz, ArH), 8.53 (1H, d, J 14 Hz, CHNH), 11.22 (1H, d, J 14 Hz,
CHNH). (4-Ethoxyphenyl)aminomethylene Meldrum’s acid (0.5 g,
1.72 mmol) was heated at reflux (sand bath) in freshly distilled diphenyl
ether (2 g) for 15 min. Addition of light petroleum (b.p. 40–60ꢁC) to the
cooledsolution failedto precipitate any material, so chloroform was
added to the light petroleum : diphenyl ether mixture, when a solid was
obtainedwhich was filteredandwashedwith further chloroform. The fil-
trate volume was reduced under reduced pressure, and the precipitation
repeatedtwice. The title compound 6a was obtainedas a pale brown pow-
dery solid (0.12 g, 37%), m.p. 249–254ꢁC (Found: Mþ 189.078. C11H11NO2
requires: M 189.079); ꢀmax (CHCl3)/cmꢀ1 3272, 2931, 1621, 1580, 1564,
1129, 1114; ꢁ (270 MHz; CDCl3) 1.51 (3H, t, J 7 Hz, CH3CH2O), 4.14
(2H, q, J 7 Hz, CH3CH2O), 7.11 (1H, d, J 6.5 Hz, 3-H), 7.43 (1H, d, J
2.5 Hz, 5-H), 7.55 (1H, dd, J 2.5 and9 Hz, 7-H), 7.83 (1H, d, J 9 Hz,
8-H), 8.30 (1H, d, J 6.5 Hz, 2-H), 10.1 (1H, br, s, NH); ꢁ (270 MHz;
d6-DMSO) 1.36 (3H, t, J 7 Hz, CH3CH2O), 4.08 (2H, q, J 7 Hz, CH3CH2O),
6.01 (1H, d, J 7 Hz, 3-H), 7.30 (1H, dd, J 3 and9 Hz, 7-H), 7.5 (2H, m, 5-H,
8-H), 7.85 (1H, d, J 7 Hz, 2-H), 11.75 (1H, br, s, NH). Flash vacuum
pyrolysis of the arylidene Meldrum’s acid (300 mg) by heating the sample
to 158ꢁC under high vꢁacuum (10ꢀ4 mbar) before passing the vapour through
a tube heatedat 650 C, also afforded 6a (76 mg, 35%), identical to that
isolated from the solution pyrolysis, as a yellow–sandy deposit on a liquid
nitrogen-cooledtrap.
2-Methyl-4-quinolone 6b and 4-methyl-2-quinolone 7: (with A.
FREEBURY andA. T. YATES) 4-Ethoxyaniline (15 g, 0.109 mol) was
added to ethyl acetoacetate (60 cm3) over 30 min andthe mixture left at
20ꢁC for 48 h. The precipitate was collectedby filtration, washedwith
hexane andrecrystallisedto affordethyl 3-(4-ethoxyphenyl)aminobut-2-
enoate (16.22 g, 60%), m.p. 46–47ꢁC (from ethanol) (Found: C, 67.60; H,
7.77; N, 5.57%. C14H19NO3 requires: C, 67.45; H, 7.68; N, 5.62%); ꢀmax
(CHCl3)/cmꢀ1 3304, 2990, 2931, 1713, 1650, 1613, 1552, 1510, 1162, 1117; ꢁ
(CDCl3) 1.25 and1.40 (each 3H, t, J 7 Hz, CH3CH2O), 1.91 (3H, s, CH3C),
4.05 and4.15 (each 2H, q, J 7 Hz, CH3CH2O), 4.65 (1H, s, CH), 6.85 and
7.00 (each 2H, d, J 9 Hz, ArH), 10.15 (1H, s, NH). This enamino-ester
(15.22 g, 0.061 mol) was added to conc. sulphuric acid (30 cm3) over
30 min, keeping the temperature below 35ꢁC. The mixture was heatedto
90–95ꢁC for 1 h, cooled, poured into ice-water and the precipitate collected
by filtration, washedwith water, then suspendedin water. The suspension

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6-ETHOXYQUINOLINES
3191
was neutralisedwith aqueous ammonia, filteredandthe precipitate washed
with water anddriedto affordthe title compound6b (7.08 g, 57%), m.p.
>230ꢁC (from methanol) (Found: Mþ 203.095. C12H13NO2 requires
M 203.095); ꢀmax (Nujol)/cmꢀ1 3250, 2924, 1615; ꢁ (CDCl3) 1.37 (3H, t, J
7 Hz, CH3CH2O), 2.37 (3H, s, CH3C), 4.12 (2H, q, J 7 Hz, CH3CH2O), 6.37
(1H, s, 3-H), 7.20 (3H, m, ArH), NH not observed. 4-Methyl-2-quinolone 7
was preparedas above from 4-ethoxyaniline andethyl acetoacetate, but
heating for 2 h at 120–140ꢁC, to afford N-(4-ethoxyphenyl)-3-oxobutana-
mide (17.2 g, 71%), m.p. 88–90ꢁC (Found: C, 65.44; H, 7.00; N, 6.32%.
C12H15NO3 requires: C, 65.14; H, 6.83; N, 6.33%); ꢀmax (CHCl3)/cmꢀ1
3305, 2930, 1713, 1647, 1598, 1556; ꢁ (CDCl3) 1.39 (3H, t, J 7 Hz,
CH3CH2O), 2.30 (3H, s, CH3CO), 3.54 (2H, s, COCH2CO), 4.00 (2H, q,
J 7 Hz, CH3CH2O) 6.81 and7.40 (each 2H, d, J 9 Hz, ArH), 9.03 (1H, s,
NH). The amide (16.2 g, 0.073 mol) was cyclised as above to afford the title
compound 7 (9.73 g, 65%), m.p. 215–217ꢁC (from methanol) (Found: Mþ
203.094. C12H13NO2 requires M 203.095); ꢀmax (Nujol)/cmꢀ1 3245, 2924,
1644, 1620, 1463; ꢁ (CDCl3) 1.35 (3H, t, J 7 Hz, CH3CH2O), 2.40 (3H, s,
CH3C), 4.05 (2H, q, J 7 Hz, CH3CH2O), 6.41 (1H, s, 3-H), 7.20 (3H, m,
ArH), NH not observed.
ACKNOWLEDGMENTS
We thank Dr. A. R. Mellersh (Derby City Hospital) for biological
data and financial assistance, and Parke-Davis Neuroscience Research
Unit for partial financial support (M. S. L.).
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2. Mellersh, A.R. Derby City Hospital UK, personal communication.
3. Campbell, K.N.; Schaffner, I.J. J. Am. Chem. Soc. 1945, 67, 86.
4. Gutzwiller, J.; Uskokovic, M. J. Am. Chem. Soc. 1970, 92, 204.
5. Cassis, R.; Tapia, R.; Valderrama, J. A. Synth. Commun. 1985, 15, 125.
6. Gordon, H.J.; Martin, J.C.; McNab, H. J. Chem. Soc., Chem.
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7. Mehrotra, S.; Barthwhal, J.P.; Pandey, B.R.; Bhargava, K.P.; Parmar,
S.S. J. Heterocycl. Chem. 1980, 17, 1213.
Receivedin the USA October 29, 2001

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