Synthesis of brequinar analogue inhibitors of malaria parasite dihydroorotate dehydrogenase

Article abstract of DOI:10.1016/j.bmc.2005.01.017

A series of 2-phenyl quinoline-4-carboxylic acid derivatives related to brequinar, an inhibitor of human dihydroorotate dehydrogenase (DHODH), has been prepared and evaluated as inhibitors of DHODH from the malaria parasite Plasmodium falciparum. Brequinar was essentially inactive against PfDHODH (IC₅₀ 880 μM) whereas several members of the series inhibited PfDHODH. Unexpectedly, replacement of the carboxylic acid required for brequinar to inhibit hDHODH was not essential in the diisopropylamides that inhibited PfDHODH.

Full text of DOI:10.1016/j.bmc.2005.01.017

Bioorganic & Medicinal Chemistry 13 (2005) 1945–1967
Synthesis of brequinar analogue inhibitors of malaria parasite
dihydroorotate dehydrogenase
Andrew N. Boa,a,* Shane P. Canavan,a Paul R. Hirst,a, Christopher Ramsey,b
Andrew M. W. Steadb,à and Glenn A. McConkeyb,*
aDepartment of Chemistry, University of Hull, Cottingham Road, Hull HU6 7RX, UK
bSchool of Biology, University of Leeds, Clarendon Way, Leeds LS2 9JT, UK
Received 24 September 2004; accepted 12 January 2005
Available online 1 February 2005
Abstract—A series of 2-phenyl quinoline-4-carboxylic acid derivatives related to brequinar, an inhibitor of human dihydroorotate
dehydrogenase (DHODH), has been prepared and evaluated as inhibitors of DHODH from the malaria parasite Plasmodium fal-
ciparum. Brequinar was essentially inactive against PfDHODH (IC50 880 lM) whereas several members of the series inhibited
PfDHODH. Unexpectedly, replacement of the carboxylic acid required for brequinar to inhibit hDHODH was not essential in
the diisopropylamides that inhibited PfDHODH.
ꢀ 2005 Elsevier Ltd. All rights reserved.
1. Introduction
pyrimidine pathway have been identified in the Plasmo-
dium falciparum genome but genes encoding enzymes in
pyrimidine salvage do not appear to be present.2 The
fourth enzyme in the biosynthetic pathway, dihydrooro-
tate dehydrogenase (DHODH), is located in the mito-
chondrial membrane where it catalyses the oxidation
of dihydroorotate to orotate. Concomitant with dihy-
droorotate oxidation is electron transfer to ubiquinone
(cofactor Q) via a flavin mononucleotide intermediate.
DHODH is one of the few targets in Plasmodium that
has been validated as a drug target.3 Human cells, in
contrast to Plasmodium, synthesise and salvage pyrim-
idines. Leflunomide4 (AravaTM) and brequinar5 (Fig. 1)
are two well-described inhibitors of human dihydrooro-
tate dehydrogenase (hDHODH), although these com-
pounds have different potencies against mouse, rat and
hDHODH. In co-crystallisation experiments with
brequinar and the active metabolite of leflunomide
(A77-1726) with human DHODH,6 both were found
to bind in a common site, that is also believed to be
the binding site of the cofactor ubiquinone. DHODH
was also originally believed to be the target of the anti-
malarial drug atovaquone (prescribed as a combination
drug MalaroneTM),7 an ubiquinone mimic, but it has been
shown that its primary site of action is probably due to
disruption of electron transport by interaction with the
cytochrome BC1 complex.8 Recently DHODH has also
served as the target for development of antimicrobial
agents. Inhibitors have been identified that inhibit
With 300–500 million cases and 1.5–2 million deaths
annually, malaria is among three of the principal infec-
tious diseases worldwide (EU-US Summit, 26 June
2004). The treatment and prevention of malaria has tra-
ditionally been through the use of chemotherapeutic
agents such as chloroquine and fansidar (a sulfadox-
ine/pyrimethamine combination) however widespread
drug resistance has rendered these agents ineffective in
many malarious regions of the world. The emergence
of drug resistance has highlighted the need for new anti-
malarial agents and the investigation of novel, exploit-
able targets within Plasmodium parasites.1 Features of
the parasite that differ from the host, such as pyrimidine
biosynthesis, offer the best prospects for development of
new antimalarial drugs. Plasmodium rely completely on
de novo pyrimidine synthesis to supply uridine mono-
phosphate (UMP), an essential nucleotide required for
growth. Genes encoding all enzymes in the conserved
*
Corresponding authors. Tel.: +44 01482 465022; fax: +44 01482
466410 (A.N.B.); tel.: +44 01133 432908; fax: +44 01133 432835
(G.A.M.); e-mail addresses: a.n.boa@hull.ac.uk; g.a.mcconkey@
leeds.ac.uk
Present address: Onyx Scientific Limited, Units 97/98, Silverbriar,
Sunderland Enterprise Park East, Sunderland SR5 2TQ, UK.
à Present address: School of Pharmacy, RCM, University of Puerto
Rico, San Juan, PR, USA.
0968-0896/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2005.01.017

1946
A. N. Boa et al. / Bioorg. Med. Chem. 13 (2005) 1945–1967
CO2Na
CH3
F
F3C
F3C
O
O
CN
OH
N
H
H3C
N
F
N
H
H3C
N
O
Brequinar
Leflunomide
A77-1726
O
OH
O
Cl
Atovaquone
Figure 1.
growth of the microorganisms Helicobacter pylori9 and
Enterococcus faecalis.10 These are being developed as
possible treatments for ulcers and dysentery respec-
tively. In light of the previous research we decided to
investigate the synthesis and evaluation of inhibitors
of dihydroorotate dehydrogenase from P. falciparum
(PfDHODH) as potential antimalarial agents, and
report herein our preliminary findings.
In order to evaluate initially as wide a range of deriva-
tives as possible based on the PQC ÔscaffoldÕ we pro-
posed a synthetic route involving two classes of key
derivatives, namely benzylic bromides and arylalde-
hydes. We made 3-, 6- and 8-methyl PQC derivatives
starting with the classical Sandmeyer isatin synthesis15
(unless they were available commercially at a reasonable
price), followed by base-catalysed Pfitzinger reaction16
to produce the quinolines 2a–d. Esterification, via the
acid chloride, and subsequent free-radical bromination
using N-bromosuccinimide (NBS) gave the benzylic bro-
mides 4a–d in good yield (Scheme 1 and Table 1).
2. Results
Initially the sensitivity of PfDHODH to brequinar was
tested, as this is one the most potent hDHODH inhibi-
tors published.11 Recombinant protein was expressed
from a synthetic PfDHODH gene in which the codon
bias has been adjusted to optimise expression in E. coli.
Expressed PfDHODH and hDHODH are similarly
truncated to remove the membrane domains and they
contain an amino-terminal histidine tag for ease of puri-
fication. Assays for DHODH activity are based on a
standard colorimetric assay that measures decreasing
absorption in the visible range as a result of reduction
of the electron acceptor dichloroindophenol. PfDHODH
was significantly less sensitive than hDHODH to inhibi-
tion (IC50 880 lM vs 0.01 lM,12 respectively). This is
similar to results with other inhibitors of human
DHODH.13 The basic brequinar skeleton, lacking the
3-methyl and two fluorine atoms, and the parent unsub-
stituted 2-phenylquinoline-4-carboxylic acid were also
prepared but showed no inhibitory activity either at
10 lM.14 These results indicated that the structure of
quinoline-based inhibitors of PfDHODH might need
to be significantly different from the brequinar structure.
The sequence and structure of PfDHODH indicate that
it contains a putative channel analogous to hDHODH
although these initial studies suggested it may have sub-
stantial alterations (Clardy, J., personal communica-
tion). Ironically, the high specificity of brequinar and
other DHODH inhibitors for hDHODH may suggest
that PfDHODH can be specifically inhibited. Hence
we decided to synthesise and test a set of quinolines
based upon the 2-phenylquinoline-4-carboxylic acid
(PQC) ÔcoreÕ of brequinar.
The 3-, 6- and 8-bromomethyl derivatives of PQC ethyl
esters were then reacted with simple nucleophiles,
mainly secondary amines but also an alcohol and a
thiol, to produce cleanly a variety of derivatives (5, 6
and 7) for which a sub-set was also converted to the
corresponding sodium carboxylates 8 (as in brequinar
sodium) (Fig. 2 and Table 2). Primary amines reacted
with the 3-bromomethyl PQC ethyl ester to give, not
unexpectedly, cyclised lactams 9. Surprisingly moderate
activity against PfDHODH was observed with lactam
O
CO2H
R3
R3
R6
O
O
R6
N
H
KOH,
EtOH, H2O
N
R8
1a-c
R8
2a-d
i, SOCl2
ii, EtOH, DCM
CO2Et
R3
CO2Et
R3
NBS, Bz2O
CCl4
R6
R6
N
N
R8
R8
4a-d
3a-d
Scheme 1.

A. N. Boa et al. / Bioorg. Med. Chem. 13 (2005) 1945–1967
1947
Table 1. Key intermediates with 2-phenylquinoline-4-carboxylic acid
core
Table 2. Alkylaminomethyl derivatives of 2-phenylquinoline-4-car-
boxylic acid
R3
R6
R8
R3
R6
H
R8
H
1a
1b
H
H
5a
5b
NCH2
CH3
H
H
1c
CH3
H
2a,3a
2b,3b
2c,3c
2d,3d
4a
CH3
H
H
H
H
H
H
NCH2
CH3
H
H
H
CH3
H
5c
8c
CH3
CH2Br
H
CH3
H
O
NCH2
H
4b
4c
CH2Br
H
CH2Br
H
5d
8d
H
CH2Br
CH2Br
H
NCH2
H
H
H
4d
N
5e
8e
NCH2
H
H
H
9a and so a few further derivatives were made in this
series.
5f
8f
NCH2
H
H
The bromomethyl PQCs 4 were then subjected to fur-
ther modifications including oxidation to provide a
new set of Ôbuilding blocksÕ based upon the aldehyde
functional group. The Hass–Bender oxidation,17 utiliz-
ing the nitropropane anion, cleanly gave the 8- and 6-
aldehydes 10b and 10c, but with 3-bromomethyl PQC
4a the isolated product was the ethoxy lactone 11
(Scheme 2). This arises from attack of ethoxide on the
newly formed aldehyde carbon, followed by attack of
the resulting oxyanion on the ethyl ester carbonyl group.
The required aldehyde–ester 10a could however have
been obtained by warming 4a DMSO for 7 min in the
presence of NaHCO3.18 Hydrolysis of the ethoxy lact-
one 11 to the hydroxy lactone 12 proceeded in quanti-
tative yield, and gave a derivative, which showed
modest inhibitory activity against PfDHODH. How-
ever, further representative derivatives in this series (13
and 14) were inactive. Interestingly, treatment of 3,6-
bis(bromomethyl) PQC 4d with 2.2 equiv of sodium
ethoxide and nitropropane gave cleanly the double
oxidised compound 15 in 65% yield. This methodology
applied to similar heterocycles would seem to hold
promise as a way to access versatile, multifunctional
scaffolds for combinatorial library construction.
5g
8g
O
NCH2
5h
8h
NCH2
H
H
H
N
5i
8i
H
NCH2
5j
8j
H
H
H
H
H
NCH2
5k
8k
O
NCH2
5l
8l
NCH2
H
H
N
6a X = O
7a X = S
p-BrC6H4XCH2
H
H
6a X = O
7a X = S
H
H
p-BrC6H4XCH2
6a X = O
7a X=S
H
p-BrC6H4XCH2
sulfur ylide chemistry. However the aldehyde–esters 10b
gave the corresponding epoxide in low yield (20%) even
For preparation of further Ôbuilding blocksÕ, the synthe-
sis of epoxides was envisaged through the application of
R4
N
O
CO2Et
CO2Na
R3
R6
R3
R6
N
N
N
R8
R8
5a-l, 6a-c, 7a-c
8c-l
9a R4 = C2H5
9b R4 = nC3H7
9c R4 = nC4H9
9d R4 = tC4H9
CO2Et
CO2Et
OHC
N
N
CHO
10b
10c
Figure 2.

1948
A. N. Boa et al. / Bioorg. Med. Chem. 13 (2005) 1945–1967
O
O
O
CO2Et
CH2Br
O
O
MeMgI
Et2O
NaOEt
Me
N
OR
Me2CHNO2
N
N
N
4a
13
11 R = OEt
12 R = OH
O
DMSO, heat
H2SO4
O
CO2Et
CHO
morpholine
EtOH
N
14
15
N
O
CO2Et
CH2Br
O
10a
NaOEt
Me2CHNO2
BrH2C
OHC
OEt
N
N
4d
Scheme 2.
after some effort at optimisation. We surmised that
amides would be more stable to the epoxidation reaction
conditions than esters. As we knew that some lactams
had shown activity (e.g., 9a) and in brequinar there is
both 3- and 6-substitution of the quinoline ring, we pre-
pared the diethyl, dibenzyl and diisopropyl amides 16 of
the 3,6-dimethyl PQC acid 2d. We encountered, how-
ever, difficulty in obtaining the range of desired benzylic
bromides as the free-radical bromination was not selec-
tive. Indeed very complex product mixtures were ob-
tained even with sub-stoichiometric amounts of NBS,
which we attributed to the involvement of radical trans-
location involving the carbon a to the nitrogen.19 Only
with the diisopropylamides of monomethyl derivatives
could the bromination be achieved cleanly and in good
yield giving 17a and 17b (Fig. 3), which were then
cleanly converted to the corresponding aldehydes 18a
and 18b using the Hass–Bender oxidation described pre-
viously. In choosing to study amides of 2d, we had also
wondered if selective 6-methyl bromination was possi-
ble, given that the 3-methyl group should be more hin-
dered due to the diisopropylamide and phenyl group.
However the amide group is essentially perpendicular
to the aromatic ring, and does not hinder the 3-methyl
group to any great extent. Restricted rotation about
the C–Ar bond in derivatives of 17/18a and 17/18b led
to some interesting stereochemical and mechanistic
studies, which we have recently reported in
communication.20
a
Conversion of the amide aldehydes 18 to their corre-
sponding epoxides 19 was, as hoped for, effected cleanly
using dimethylsulfonium methylide in tert-butanol. H
1
NMR showed epoxide 19b, and derivatives obtained
therefrom, to be a 1:1 mixture of diastereoisomeric con-
formers distinguishable on the NMR timescale due to
the restricted rotation about the CAr–C@O bond. Epox-
ide 19a was obtained a mixture of atropisomers (dia-
stereoisomeric conformers with a half-life of 1000 s
or more) ranging from about 5 to 6:1.20
Epoxides 19a and 19b served as precursors to hydroxy-
ethylquinolines through nucleophilic ring opening of the
epoxides (Scheme 3). In the case of epoxide 19b, reaction
by heating with secondary amines in ethanol gave the
expected 6-(20-amino-10-hydroxyethyl)quinolines 20
CONiPr2
CH2Br
CONiPr2
N
CONR2
Me
Me
BrH2C
N
N
16a, R = Bn; 16b, R = Et; 16c, R = iPr
17b
17a
CONiPr2
i
CONiPr2
CONPr2
N
CONiPr2
N
O
O
CHO
OHC
N
N
18a
18b
19a
19b
Figure 3.

A. N. Boa et al. / Bioorg. Med. Chem. 13 (2005) 1945–1967
1949
NiPr2
OH
O
R2N
HO
20a-c
21b-c
R2NH
EtOH
NiPr2
N
Ph
Ph
O
O
NiPr2
NR2
O
N
Ph
19b
R2NLi
THF
O
N
N
a, R2N = Et2N b, R2N =
NiPr2
c, R2N =
N
OH
O
R2NH
EtOH
NR2
22a-c
23b-c
NiPr2
N
Ph
O
O
NiPr2
NR2
O
N
Ph
OH
19a
R2NLi
THF
N
Ph
Scheme 3.
along with the opposite regioisomer 21 as a minor prod-
uct (ꢀ10:1). Reaction of 19b with lithium amides at
room temperature however gave exclusively the regio-
isomer 21.20 Similar results were obtained in the reaction
of epoxide 20a where the reaction with three secondary
amines in ethanol gave the amino alcohols 22, this time
exclusively as might be expected due to the increased ste-
ric hindrance at the reaction centre. Regioisomers of the
amino alcohols (20/21; 22/23) were easily separable by
column chromtaography, but clearly the diastereoiso-
meric conformers were not. Therefore racemic mixtures
of 20 and 21 were assayed against PfDHODH, as were
mixtures of both enantiomers of the atropisomers of
22 and 23.
against PfDHODH had similar activity or exhibited
some preference for inhibiting the parasite versus human
DHODH. This supports our hypothesis that inhibitors
can be developed that take advantage of differences
between the parasite and human DHODH.
Lead compounds identified in the preliminary screen
were tested for antiplasmodial activity in a standard
microtitre growth assay, utilising the incorporation of
3H-hypoxanthine as a marker of parasite viability. Com-
pound concentrations were tested in a range of 0.01–
100 lM in individual incubations in triplicate.21 Inhibi-
tor efficacy was assessed using comparisons of concen-
trations causing 50% inhibition of parasite growth, as
shown in Figure 4. The compounds were active against
P. falciparum growth in the micromolar range with
20a the most active compound (IC50 0.9 lM). The com-
pounds were also tested against a strain of P. falciparum
that is resistant to chloroquine and mefloquine (W2mef).
Naturally, all the brequinar analogues prepared contain
a quinoline ring and as such are closely related to chlo-
roquine. This quinoline-based drug is the most used
antimalarial drug worldwide and is now suffering from
the rampant rise of resistant parasites, but there was
no appreciable difference detected between the drug-
sensitive and drug-resistant strains in their sensitivity
to 5k, 12, 20a and 20b.
Compounds showing some level of inhibition of
PfDHODH (>10% at 10 lM) were tested for a full
IC50 with enzyme. Inhibition curves were determined
for four active compounds 5k, 12, 20a and 20b (Table
3). They exhibited a range of activities (38–435 lM)
but were all substantially more active than brequinar.
The active compounds were also tested for their activity
against human DHODH. The derivatives were consider-
ably less active against human DHODH than brequinar
(IC50 values between 38 and 480 lM). As shown in
Table 3, two of the derivatives selected for activity
Table 3. IC50 values for selected inhibitors of P. falciparum and human
DHODH
3. Discussion
Compound
IC50 (lM)
PfDHODH
hDHODH
The set of quinoline derivatives in this study revealed
some which were found to be inhibitors of PfDHODH
(Table 3). We had also prepared and tested the related
2-(p-aminophenyl)quinoline-4-carboxylic acid,22 but this
was inactive. This is not unexpected as the PfDHODH
ubiquinone channel is likely to be hydrophobic as in
Brequinar
5k
12
888
38
0.0112
38
80
162
435
160
20a
20b
335
480

1950
A. N. Boa et al. / Bioorg. Med. Chem. 13 (2005) 1945–1967
100
90
80
70
60
50
40
30
20
10
0
100
90
80
70
60
50
40
30
20
10
0
0.01
0.1
1
5k
10
(µM)
100
1000
0.01
0.1
1
12
10
(µM)
100
1000
100
90
80
70
60
50
40
30
20
10
0
100
90
80
70
60
50
40
30
20
10
0
0.01
0.1
1
20a
10
(µM)
100
1000
0.01
0.1
1
10
(µM)
100
1000
20b
Figure 4. Dose–response plots of the antiplasmodial activity of selected compounds against P. falciparum strains 3D7 (Ç) and W2 mef (j).
human DHODH, and the amino group will be charged
at physiological pH. Although many members of this
first set of derivatives were not significantly active 5k
inhibited PfDHODH with an IC50 of 38 lM. Primary
amines reacted with the 3-bromomethyl PQC ethyl ester
4a to yield cyclised lactams of which the N-ethyl deriva-
tive 9a exhibited some inhibitory activity. This indicates
that the carboxylate may not be essential for inhibitory
activity against the parasite enzyme (in contrast to
hDHODH), though only derivatives with small aliphatic
groups attached to the lactam nitrogen appeared to have
any detectable activity at 10 lM. Of the amino alcohol
series (20–23) only derivatives 20a and 20b showed some
level of activity at concentrations tested. Derivative 20b
however showed selective inhibition of PfDHODH and,
given that it was tested as a mixture of enantiomers, it
may well be that the activity of one isomer would be
greater than the 160 lM found. However, as the IC50
values determined were quite modest we did not
consider the preparation of single enantiomers of these
products to be pressing at this time.
nation treatments with an inhibitor of heme degradation
(data not shown). Differences between results with en-
zyme and parasite growth are most likely due to assay
differences soluble recombinant enzyme and mem-
brane-bound mitochondrial protein. Although the inhi-
bition of the parasites roughly correlates with effects on
DHODH, unexpectedly the IC50 values for the parasites
are lower than the enzyme levels. This may be due to dif-
ferences between in vitro assay conditions and in vivo
activity. The recombinant enzyme is soluble with its
membrane-binding domain cleaved, and assays are per-
formed in aqueous conditions with a synthetic coenzyme
Q as an electron acceptor whereas in vivo the enzyme is
bound to the inner mitochondrial membrane and utilises
an extended coenzyme Q. Alternatively the inhibitors
are concentrated in the parasite or the compounds inter-
act with heme metabolism in the parasites due to p–p
stacking of the quinoline.
4. Conclusions
Compounds active in inhibiting PfDHODH were also
active against drug-sensitive and chloroquine- and
mefloquine-resistant parasites. Although there are
differences between the inhibition of PfDHODH and
sensitivity of parasites, this cannot be readily explained
as inhibition of heme polymerisation, analogous to chlo-
roquine, because the compounds are similarly active
against CQ-sensitive and CQ-resistant P. falciparum
strains and there is not significant antagonism in combi-
Starting with a skeletal structure of the inhibitor brequ-
inar, that binds in a channel in hDHODH but does not
inhibit PfDHODH, several compounds that inhibit
PfDHODH were identified from a set of quinoline deriv-
atives. The amino alcohol 20b shows moderate selective
inhibition against the plasmodial versus human enzyme,
compared to the specificity of the starting compound
brequinar, although the necessity of high selectivity for
the parasite enzyme is debatable since high potency

A. N. Boa et al. / Bioorg. Med. Chem. 13 (2005) 1945–1967
1951
human DHODH inhibitors are in clinical use. This
demonstrates that parasite-specific inhibitors can be
identified and will serve as a template for the design of
more potent, specific derivatives that can be tested
against growing parasites. Observation that amides
(and lactams) of 2-phenylquinoline 4-carboxylic acids
can have micromolar activity contrasts the results found
for brequinar. The positive results for 20a,b and lactams
such as 9a indicate that derivatives can bind in a
completely different orientation to that of brequinar or
that they bind at a different site. Differentiating these
possibilities will probably require X-ray data for
PfDHODH,23 co-crystallisation studies in addition to
full kinetic analysis and modelling of the enzyme.
was warmed to 70–75 ꢁC for 10 min before being cooled
to room temperature. The solution was added to ice/
water (230 mL) and the resulting precipitate filtered
and washed with cold water until free of acid. The crude
product was recrystallised from three times its weight of
acetic acid, washed with cold water and dried in vacuo
(P2O5) to yield the title compound (9.06 g, 74%) as dark
red crystals. Mp 182–184 ꢁC (lit.24 184 ꢁC); dH
(400 MHz; CDCl3): 2.33 (3H, s, CH3), 6.83 (1H, d,
Ar–Hc), 7.37 (1H, dd, Ar–Hb), 7.42 (1H, s, Ar–Ha),
8.29 (1H, s, NH); m/z 161 (M+, 45), 133 (100), 104
(75), 78 (35).
5.2. 7-Methyl-1H-indole-2,3-dione (1c)
Using the same method as above, chloral hydrate
(22.74 g, 0.138 mol) in water (300 mL), sodium sulfate
(105 g, 0.76 mol), a solution of o-toluidine (13.5 g,
0.125 mol) in water (75 mL) and concentrated hydro-
chloric acid (12.8 g) and a solution of hydroxylamine
hydrochloride (27.45 g, 0.395 mol) in water (125 mL)
were heated at reflux for 1–2 min. The isonitrosoacetan-
ilide (13.0 g, 59%) was obtained as a light brown solid.
Mp 119–121 ꢁC (lit.15 121 ꢁC). Using the same method
as for the synthesis of methylisatin (1b), the isonitroso-
acetanilide (22.0 g, 0.12 mol) was added to concentrated
sulfuric acid (100 mL). The crude product was filtered,
washed with cold water until free of acid and dried in va-
cuo (P2O5) to yield the title compound (13.82 g, 69%) as
a pale orange solid. Mp 266–268 ꢁC (lit.25 270–273 ꢁC);
dH (400 MHz; CDCl3): 2.25 (3H, s, CH3), 6.97 (1H, t,
Ar–Hb), 7.34 (2H, d, Ar–Ha + Ar–Hc), 10.98 (1H, s,
NH); m/z 161 (M+, 35), 133 (30), 104 (100), 78 (35).
5. Experimental
Diethyl ether and THF, used as reaction solvents, were
dried over and distilled from sodium wire before use.
Ethanol was dried over and distilled from magnesium
turnings, and DCM was dried over and distilled from
calcium hydride. All other solvents and reagents were
used as purchased. Reactions were monitored by thin
layer chromatography using aluminium-backed plates
coated with silica gel (60 F254 Merck), and purification
of products by column chromatography was accom-
plished using silica gel 60 (200–400 mesh) from a variety
of suppliers. Spectra were recorded using a JEOL
1
Lambda 400 spectrometer for H NMR spectra, either
a Perkin–Elmer 880 spectrophotometer or Perkin–Elmer
1000 Fourier Transform (FT-IR) spectrophotometer for
IR, and either a Finnigan-MAT 1020 GC/MS or a
QP5050A Shimadzu GC/MS spectrometer for mass
spectra. Elemental analysis was carried out using a
Fisons EA 1108 CHN machine, and in some cases vana-
dium pentoxide was added to aid combustion. Melting
points were measured using a Gallenkamp melting point
apparatus in open capillaries and are not corrected.
5.3. 3-Methyl-2-phenyl-quinoline-4-carboxylic acid (2a)
Potassium hydroxide (110.85 g, 1.98 mol) in water
(225 mL) was added dropwise to isatin (1a) (48.54 g,
0.33 mol) in ethanol (540 mL) over 15 min. Propiophe-
none (44.28 g, 0.33 mol) was added and the reaction
was heated under reflux for 18 h, cooled to room tem-
perature and solvent removed in vacuo. The resulting
solid was dissolved in water, washed with diethyl ether
(3 · 150 mL), cooled in ice/water and acidified with ace-
tic acid. The crude product was filtered and recrystal-
lised from acetic acid. After washing with cold diethyl
ether (3 · 100 mL) and drying in vacuo (P2O5) the title
compound (71.6 g, 82%) was obtained as a white solid.
Mp 294–297 ꢁC (lit.26 306 ꢁC); dH (400 MHz; CDCl3):
2.44 (3H, s, CH3), 7.54 (6H, m, 5Ar–H + Ar–Hb or
Ar–Hc), 7.72 (1H, t, Ar–Hb or Ar–Hc), 7.89 (1H, d,
Ar–Ha or Ar–Hd, Jab or Jdc 8.3 Hz), 8.08 (1H, d, Ar–
Ha or Ar–Hd, Jab or Jdc 8.5 Hz); IR (KBr) mmax 1711,
1295, 1245, 769, 725; m/z 262 (M+, 100), 217 (20), 108
(15).
5.1. 5-Methyl-1H-indole-2,3-dione (1b)
To chloral hydrate (22.74 g, 0.138 mol) in water
(300 mL) was added sodium sulfate (130 g, 0.92 mol),
a solution of p-toluidine (13.5 g, 0.125 mol) in water
(75 mL) and concentrated hydrochloric acid (12.8 g),
and
a
solution of hydroxylamine hydrochloride
(27.45 g, 0.395 mol) in water (125 mL). The mixture
was heated under reflux for 1–2 min before being cooled
rapidly in an ice/salt bath. The crude product was fil-
tered and washed with cold water. The resulting solid
was dissolved in 1.5 M sodium hydroxide solution
(100 mL), filtered to remove any insoluble impurities
and acidified with 2 M hydrochloric acid. The precipi-
tate was filtered, washed with cold water and dried in
vacuo to yield the isonitrosoacetanilide (13.66 g, 61%)
as a pale brown solid. Mp 158–160 ꢁC (lit.15 162 ꢁC);
dH (400 MHz; CDCl3): 2.32 (3H, s, CH3), 7.13 (2H, d,
Ar–H), 7.43 (1H, s, CH@N), 7.49 (2H, d, Ar–H), 8.62
(1H, s, NOH), 11.72 (1H, s, NH). The isonitrosoacetan-
ilide (13.6 g, 0.076 mol) was added to concentrated sul-
furic acid (70 mL) in portions over 30–35 min keeping
the temperature between 50 and 60 ꢁC. The reaction
5.4. 6-Methyl-2-phenyl-quinoline-4-carboxylic acid (2b)
Using the same method as for the synthesis of carboxylic
acid (2a), potassium hydroxide (62.9 g, 1.12 mol) in
water (135 mL), methylisatin (1b) (30.0 g, 0.186 mol)
in ethanol (300 mL) and acetophenone (22.36 g,
0.186 mol) were heated under reflux for 18 h. After

1952
A. N. Boa et al. / Bioorg. Med. Chem. 13 (2005) 1945–1967
addition of the acetic acid the crude product was washed
with cold diethyl ether (100 mL) and dried in vacuo
(P2O5) to yield the title compound as an off white solid
(44.0 g, 90%). Mp 225–227 ꢁC (lit.27 228 ꢁC); dH
(400 MHz; CDCl3): 2.60 (3H, s, CH3), 7.51 (3H, m,
3Ar–H), 7.63 (1H, dd, Ar–Hc, Jcb 1.7 Hz, Jcd 8.5 Hz),
8.16 (1H, d, Ar–Hd, Jdc 8.5 Hz), 8.20 (2H, m, 2Ar–H),
8.51 (1H, s, Ar–Ha), 8.62 (1H, s, Ar–Hb); IR (KBr) mmax
1713, 1599, 1413, 1379, 1155; m/z 263 (M+, 80), 218
(100), 108 (25).
pound (24.0 g, 73%) as a yellow oil. Rf 0.30 [DCM];
dH (400 MHz; CDCl3): 1.49 (3H, t, O–CH2CH3), 2.87
(3H, s, CH3), 4.59 (2H, q, O–CH2–CH3), 7.51 (6H, m,
5Ar–H + Ar–Hb or Ar–Hc), 7.70 (1H, t, Ar–Hb or
Ar–Hc), 7.75 (1H, d, Ar–Ha or Ar–Hd, Jab or Jdc
8.3 Hz), 8.15 (1H, d, Ar–Ha or Ar–Hd, Jab or Jdc
7.8 Hz); IR (KBr) mmax 2987, 1725 (ester), 1228, 1058,
762, 706; m/z 291 (M+, 95), 262 (100), 215 (20).
5.8. 6-Methyl-2-phenyl-quinoline-4-carboxylic acid ethyl
ester (3b)
5.5. 8-Methyl-2-phenyl-quinoline-4-carboxylic acid (2c)
Using the same method as for the synthesis of ethyl ester
(3a), carboxylic acid (2b) (13 g, 4.9 · 10ꢁ2 mol) was
heated at reflux in thionyl chloride (100 mL) for 3 h.
The acid chloride stirred at room temperature with tri-
ethylamine (19.8 g, 0.196 mol) in ethanol (150 mL) for
3 h. The crude product, which crystallised on standing
was filtered, washed with cold ethanol (2 · 30 mL) and
dried in vacuo (P2O5) to yield the title compound
(10.4 g, 73%) as a white solid. Rf 0.62 [DCM–hexane
(2:1)]; Mp 72–73 ꢁC (lit.28 74–76 ꢁC); dH (400 MHz;
CDCl3): 1.50 (3H, t, O–CH2CH3), 2.59 (3H, s, CH3),
4.54 (2H, q, O–CH2–CH3), 7.51 (3H, m, 3Ar–H), 7.60
(1H, dd, Ar–Hc, Jcb 1.7 Hz, Jcd 8.5 Hz), 8.12 (1H, d,
Ar–Hd, Jdc 8.5 Hz), 8.18 (2H, m, 2Ar–H), 8.35 (1H,
s, Ar–Ha), 8.51 (1H, s, Ar–Hb); IR (KBr) mmax 1705
(ester), 1373, 1235; m/z 291 (M+, 15), 262 (10), 218
(100), 203 (25), 189 (10), 115 (80), 103 (95).
Using the same method as for the synthesis of carboxylic
acid (2a), potassium hydroxide (16.69 g, 0.298 mol) in
water
(36 mL),
7-methylisatin
(1c)
(8.0 g,
4.96 · 10ꢁ2 mol) in ethanol (80 mL) and acetophenone
(5.96 g, 4.96 · 10ꢁ2 mol) were heated under reflux for
18 h. After addition of the acetic acid the crude product
was washed with cold diethyl ether (100 mL) and dried
in vacuo (P2O5) to yield the title compound as an off
white solid (10.2 g, 78%). Mp 244–247 ꢁC (lit.28
250 ꢁC); dH (400 MHz; CDCl3): 2.80 (3H, s, CH3),
7.54 (4H, m, 3Ar–H + Ar–Hc), 7.67 (1H, d, Ar–Hd,
Jdc 7.1 Hz), 8.31 (2H, m, Ar–H), 8.38 (1H, s, Ar–Ha),
8.41 (1H, d, Ar–Hb, Jbc 9.3 Hz); IR (KBr) mmax 2926,
1699, 1271, 764; m/z 263 (M+, 100), 218 (25), 204 (10).
5.6. 3,6-Dimethyl-2-phenyl-quinoline-4-carboxylic acid (2d)
Using the same method as for the synthesis of carboxylic
acid (2a), potassium hydroxide (16.69 g, 0.298 mol) in
water (36 mL), 5-methylisatin (1b) (8.0 g, 4.96 ·
10ꢁ2 mol) in ethanol (80 mL) and propiophenone
(6.64 g, 4.96 · 10ꢁ2 mol) were heated under reflux for
18 h. After addition of the acetic acid the crude product
was washed with cold diethyl ether (100 mL) and dried
in vacuo (P2O5) to yield the title compound as an off
white solid (10.0 g, 73%). Mp >300 ꢁC; dH (400 MHz;
CDCl3): 2.39 (3H, s, CH3), 2.60 (3H, s, CH3), 7.46
(6H, m, Ar–H), 7.74 (1H, s, 7Ar–H), 7.87 (1H, d, Ar–
H); IR (KBr) mmax 1709, 1293, 1247, 764, 725; m/z 277
(M+, 70), 276 (100), 230 (25), 114 (40).
5.9. 8-Methyl-2-phenyl-quinoline-4-carboxylic acid ethyl
ester (3c)
Using the same method as for the synthesis of ethyl ester
(3a), carboxylic acid (2c) (20 g, 7.6 · 10ꢁ2 mol) was
heated at reflux in thionyl chloride (150 mL) for 3 h.
The acid chloride was stirred at room temperature in
ethanol (200 mL) and triethylamine (23.06 g,
0.228 mol) for 3 h. The crude product was purified
through a pad of silica [DCM > DCM–ethyl acetate
(1:1)] and dried in vacuo to give the title compound
(16.8 g, 76%) as an off white solid. Rf 0.84 [DCM]; Mp
70–72 ꢁC (lit.28 72 ꢁC); dH (400 MHz; CDCl3): 1.50
(3H, t, O–CH2CH3), 2.91 (3H, s, CH3), 4.53 (2H, q,
O–CH2–CH3), 7.53 (4H, m, 3Ar–H + Ar–Hc), 7.60
(1H, d, Ar–Hd, Jdc 7.1 Hz), 8.28 (2H, m, 2Ar–H), 8.38
(1H, s, Ar–Ha), 8.53 (1H, d Ar–Hb, Jbc 8.3 Hz); IR
(KBr) mmax 1731 (ester), 1251, 1205, 1100, 772; m/z 291
(M+, 100), 263 (60), 218 (25), 109 (35).
5.7. 3-Methyl-2-phenyl-quinoline-4-carboxylic acid ethyl
ester (3a)
Thionyl chloride (200 mL) was added drop wise to car-
boxylic acid (2a) (30.0 g, 0.114 mol) and the reaction
heated under reflux in a N2 atmosphere for 3 h. This
was cooled to room temperature and the thionyl chlor-
ide removed in vacuo. The last traces of thionyl chlor-
ide were removed with diethyl ether (2100 mL) to leave
the acid chloride as a yellow solid. Triethylamine
(46.1 g, 0.456 mol) in ethanol (250 mL) was added drop
wise to the acid chloride and the reaction was stirred at
room temperature for 18 h. Ice/water (300 mL) was
added, the product was extracted into DCM
(3 · 200 mL) and the organic layer dried over magne-
sium sulfate prior to filtration and removal of the sol-
vent in vacuo. The crude product was purified by
column chromatography [DCM > DCM–ethyl acetate
(6:1)] and dried in vacuo (P2O5) to yield the title com-
5.10. 3,6-Dimethyl-2-phenyl-quinoline-4-carboxylic acid
ethyl ester (3d)
Using the same method as for the synthesis of ethyl ester
(3a), carboxylic acid (2d) (3.57 g, 1.28 · 10ꢁ2 mol) was
heated at reflux in thionyl chloride (30 mL) for 3 h.
The acid chloride was stirred at room temperature
in ethanol (30 mL) and triethylamine (3.88 g,
3.84 · 10ꢁ2 mol) for 18 h. The crude product was puri-
fied through a pad of silica [DCM > DCM–ethyl acetate
(1:1)] and dried in vacuo (P2O5) to give the title com-
pound (3.5 g, 89%) as an off white solid. Rf 0.49
[DCM–ethyl acetate (19:1)]; Mp 102–104 ꢁC; dH

A. N. Boa et al. / Bioorg. Med. Chem. 13 (2005) 1945–1967
1953
(400 MHz; CDCl3): 1.49 (3H, t, O–CH2 CH3), 2.39 (3H,
s, CH3), 2.54 (3H, s, CH3), 4.59 (2H, q, O–CH2–CH3),
7.48 (7H, m, 7Ar–H), 8.02 (1H, d, Ar–H); IR (KBr) mmax
1728 (ester), 1288, 1228; m/z 305 (M+, 55), 277 (100),
230 (55), 217 (50), 115 (40).
was heated at reflux in carbon tetrachloride (200 mL)
with NBS (10.75 g, 6.0 · 10ꢁ2 mol) and benzoyl perox-
ide (1.38 g, 5.7 · 10ꢁ3 mol) for 4 h. The crude product
was recrystallised from ethanol and dried in vacuo
(P2O5) to yield the title compound (7.16 g, 72%) as fine
white solid. Rf 0.65 [hexane–ethyl acetate (3:1)]; Mp
83–85 ꢁC; (Found: C, 61.39%; H, 4.28%; N, 4.00%.
C19H16NO2Br requires: C, 61.63%; H, 4.36%; N,
3.78%); dH (400 MHz, CDCl3): 1.50 (3H, t, O–CH2-
CH3), 4.54 (2H, q, O–CH2–CH3), 5.33 (2H, s, CH2Br),
7.53 (4H, m, 3Ar–H + Ar–Hc), 7.87 (1H, dd, Ar–Hd,
Jdc 7.1 Hz, Jdb 1.0 Hz), 8.32 (2H, m, 2Ar–H), 8.41
(1H, s, Ar–Ha), 8.71 (1H, dd, Ar–Hb, Jbc 8.6 Hz, Jbd
1.2 Hz); IR (KBr) mmax 1725 (ester), 1244, 1204, 766;
m/z 371 (M+, 25), 369 (M+, 25), 290 (100), 262 (45),
108 (20).
5.11. 3-Bromomethyl-2-phenyl-quinoline-4-carboxylic
acid ethyl ester (4a)
Carbon tetrachloride (300 mL) was added to ethyl ester
(3a) (23.17 g, 7.95 · 10ꢁ2 mol), NBS (15.57 g, 8.75 ·
10ꢁ2 mol) and benzoyl peroxide (1.93 g, 7.95 · 10ꢁ3 mol).
The reaction was heated under reflux in a N2 atmo-
sphere in the presence of a heat lamp for 12 h, cooled
to room temperature and insoluble succinimide filtered
off. The filtrate was collected and the solvent removed
in vacuo to give the crude product. This was recrystal-
lised from ethanol and dried in vacuo (P2O5) to yield
the title compound (23.7 g, 81%) as fine white needles.
Rf 0.70 [hexane–ethyl acetate (2:1)]; Mp 118–122 ꢁC;
(Found: C, 61.79%; H, 4.35%; N, 3.77%. C19H16NO2Br
requires: C, 61.63%; H, 4.36%; N, 3.78%); dH (400 MHz,
CDCl3): 1.54 (3H, t, O–CH2CH3), 4.66 (2H, q, O–CH2–
CH3), 4.69 (2H, s, CH2Br), 7.52 (3H, m, 3Ar–H), 7.62
(1H, t, Ar–Hb or Ar–Hc), 7.70 (2H, m, 2Ar–H), 7.78
(1H, t, Ar–Hb or Ar–Hc), 7.87 (1H, d, Ar–Ha or Ar–
Hd, Jab or Jdc 8.6 Hz), 8.16 (1H, d, Ar–Ha or Ar–Hd,
Jab or Jdc 8.6 Hz); dC (100 MHz, CDCl3): 14.39, 27.48,
62.64, 123.48, 124.93, 125.90, 127.93, 128.63, 128.76,
129.01, 130.05, 130.81, 139.34, 140.89, 147.50, 159.94,
166.86; IR (KBr) mmax 1727 (ester), 1236, 770, 702; m/z
371 (M+, 15), 369 (M+, 15), 290 (95), 262 (100), 216
(85), 108 (45).
5.14. 6-Bromomethyl-3-methyl-2-phenyl-quinoline-4-
carboxylic acid ethyl ester, 3,6-bis-bromomethyl-2-
phenyl-quinoline-4-carboxylic acid ethyl ester (4d) and
3-bromomethyl-6-dibromomethyl-2-phenyl-quinoline-
4-carboxylic acid ethyl ester
Using the same method as for the synthesis of benzylic
bromide (4a), ethyl ester (3d) (1.0 g, 3.28 · 10ꢁ3 mol)
was heated at reflux in carbon tetrachloride (50 mL)
with NBS (0.87 g, 4.91 · 10ꢁ3 mol) and benzoyl perox-
ide (0.08 g, 3.28 · 10ꢁ4 mol) for 4 h. Column chroma-
tography [DCM–hexane (1:2) > (5:1)] was used to
obtain the title compounds.
6-Bromomethyl-3-methyl-2-phenyl-quinoline-4-carboxylic
acid ethyl ester, 3,6-bis-bromomethyl-2-phenyl-quinoline-
4-carboxylic acid ethyl ester (4d): colourless oil
(0.15 g, 12%); Rf 0.22 [DCM–hexane (6:1)]; dH
(400 MHz, CDCl3): 1.50 (3H, t, O–CH2CH3), 2.43
(3H, s, CH3), 4.60 (2H, q, O–CH2–CH3), 4.66 (2H, s,
CH2Br), 7.51 (5H, m, 5Ar–H), 7.72 (2H, m, 2Ar–H),
8.13 (1H, d, Ar–H); IR (KBr) mmax 1732 (ester), 1231,
1204; m/z 385 (M+, 10), 383 (M+, 10), 306 (M, 100),
304 (100), 276 (30), 230 (30); (4d); white solid (0.85 g,
56%); Rf 0.44 [DCM–hexane (6:1)]; Mp 120–122 ꢁC;
(Found: C, 51.69%; H, 3.43%; N, 2.82%. C20H17NO2Br2
requires: C, 51.86%; H, 3.70%; N, 2.82%); dH (400 MHz,
CDCl3): 1.55 (3H, t, O–CH2CH3), 4.66 (2H, s, CH2Br),
4.68 (2H, q, O–CH2–CH3), 4.69 (2H, s, CH2Br), 7.52
(3H, m, 3Ar–H), 7.68 (2H, m, 2Ar–H), 7.80 (1H, dd,
Ar–Hb, Jba 2.2 Hz, Jbc 8.8 Hz), 7.84 (1H, d, Ar–Ha,
Jab 2.2 Hz), 8.14 (1H, d, Ar–H, Jcb 8.8 Hz); dC
(100 MHz, CDCl3): 14.39, 27.29, 32.92, 62.81, 123.27,
124.73, 126.60, 128.66, 128.71, 129.12, 130.83, 131.79,
137.47, 139.14, 140.67, 147.17, 160.49, 166.55; IR
(KBr) mmax 1725 (ester), 1288, 1236, 696; m/z 465 (M+,
5), 463 (M+, 10), 461 (M+, 5), 384 (100), 382 (100),
275 (45), 230 (65), 149 (55).
5.12. 6-Bromomethyl-2-phenyl-quinoline-4-carboxylic
acid ethyl ester (4b)
Using the same method as for the synthesis of benzylic
bromide (4a), ethyl ester (3b) (7.95 g, 2.7 · 10ꢁ2 mol)
was heated at reflux in carbon tetrachloride (150
mL) with NBS (5.34 g, 3.0 · 10ꢁ2 mol) and benzoyl
peroxide (0.7 g, 2.8 · 10ꢁ3 mol) for 4 h. The crude prod-
uct was recrystallised from ethanol and dried in vacuo
(P2O5) to yield the title compound (7.16 g, 72%) as fine
white needles. Rf 0.69 [hexane–ethyl acetate (3:1)]; Mp
107–108 ꢁC; (Found: C, 61.38%; H, 4.20%; N, 3.69%.
C19H16NO2Br requires: C, 61.63%; H, 4.36%;
N, 3.78%); dH (400 MHz, CDCl3): 1.51 (3H, t,
O–CH2CH3), 4.55 (2H, q, O–CH2–CH3), 4.71 (2H, s,
CH2Br), 7.53 (3H, m, 3Ar–H), 7.80 (1H, dd, Ar–Hc,
Jcb 1.8 Hz, Jcd 8.5 Hz), 8.20 (3H, m, 2Ar–H + Ar–Hd),
8.41 (1H, s, Ar–Ha), 8.80 (1H, d, Ar–Hb, Jbc 1.8 Hz);
dC (100 MHz, CDCl3): 14.43, 33.64, 62.11, 120.78,
123.95, 125.53, 127.62, 129.04, 130.04, 131.01, 135.94,
137.31, 138.48, 148.86, 157.26, 166.11; IR (KBr) mmax
2983, 1726 (ester), 1253, 1158, 1034; m/z 371 (M+, 10),
369 (M+, 10), 290 (100), 262 (30), 216 (15), 108 (15).
3-Bromomethyl-6-dibromomethyl-2-phenyl-quinoline-4-
carboxylic acid ethyl ester: white solid (0.25 g, 14%); Rf
0.58 [DCM–hexane (6:1)]; Mp 136–138 ꢁC; (Found: C,
44.48%; H, 2.97%; N, 2.62%. C20H16NO2Br3 requires:
C, 44.32%; H, 2.98%; N, 2.58%); dH (400 MHz, CDCl3):
1.56 (3H, t, O–CH2CH3), 4.68 (2H, q, O–CH2–CH3),
4.69 (2H, s, CH2Br), 6.81 (1H, s, CHBr2), 7.53 (3H,
5.13. 8-Bromomethyl-2-phenyl-quinoline-4-carboxylic
acid ethyl ester (4c)
Using the same method as for the synthesis of benzylic
bromide (4a), ethyl ester (3c) (16.0 g, 5.5 · 10ꢁ2 mol)

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A. N. Boa et al. / Bioorg. Med. Chem. 13 (2005) 1945–1967
m, 3Ar–H), 7.68 (2H, m, 2Ar–H), 7.91 (1H, d, Ar–Ha,
Jab 2.2 Hz), 8.07 (1H, dd, Ar–Hb, Jba 2.2 Hz, Jbc
8.9 Hz), 8.20 (1H, d, Ar–Hc, Jcb 8.9 Hz); dC
(100 MHz, CDCl3): 14.41, 27.08, 40.19, 62.94, 121.56,
122.46, 127.23, 128.67, 128.70, 129.25, 129.78, 131.30,
138.93, 140.89, 141.05, 147.63, 161.25, 166.28; IR
(KBr) mmax 3445, 1720 (ester), 1289, 1232, 701, 674;
m/z 545 (M+), 543 (M+), 541 (M+), 539 (M+), 462
(100), 354 (20), 308 (25), 228 (25).
5.17. 3-Morpholin-4-ylmethyl-2-phenyl-quinoline-4-carb-
oxylic acid ethyl ester (5c)
Using the same method as for the synthesis of amine
(5a), morpholine (1.41 g, 1.62 · 10ꢁ2 mol) and benzylic
bromide (4a) (3.0 g, 8.1 · 10ꢁ3 mol) in toluene (40 mL)
were stirred at room temperature for 24 h. Purification
of the crude product by column chromatography
[DCM > DCM–ethyl acetate (4:1)] and drying in vacuo
(P2O5) gave the title compound (2.5 g, 83%) as a white
solid. Rf 0.15 [DCM]; Mp 102–104 ꢁC; (Found: C,
73.41%; H, 6.54%; N, 7.46%. C23H24N2O3 requires: C,
73.38%; H, 6.43%; N, 7.44%); dH (400 MHz, CDCl3):
1.50 (3H, t, O–CH2–CH3), 2.31 (4H, t, 2 · N–CH2–
CH2–O), 3.58 (4H, t, 2 · N–CH2–CH2–O), 3.71 (2H, s,
quinoline–CH2–N), 4.54 (2H, q, O–CH2–CH3), 7.48
(5H, m, 5Ar–H), 7.59 (1H, t, Ar–Hb or Ar–Hc), 7.74
(1H, t, Ar–Hb or Ar–Hc), 7.91 (1H, d, Ar–Ha or Ar–
Hd, Jab or Jdc 7.8 Hz), 8.15 (1H, d, Ar–Ha or Ar–Hd,
Jab or Jdc 8.5 Hz); dC (100 MHz, CDCl3): 14.38, 53.04,
57.49, 61.61, 66.76, 123.91, 124.38, 127.03, 127.46,
128.37, 128.48, 129.08, 129.85, 129.93, 139.89, 140.35,
147.11, 160.60, 167.93; IR (KBr) mmax 2807, 1734 (ester),
1216, 1113, 781; m/z 376 (M+, 15), 347 (20), 289 (25),
260 (35), 216 (100).
5.15. 3-Diethylaminomethyl-2-phenyl-quinoline-4-carb-
oxylic acid ethyl ester (5a)
Diethylamine (0.59 g, 8.1 · 10ꢁ3 mol) was added to benz-
ylic bromide (4a) (1.5 g, 4.05 · 10ꢁ3 mol) in toluene
(20 mL) and the reaction stirred at room temperature
for 24 h. The insoluble amine salt was removed by filtra-
tion, the solvent removed in vacuo and the resulting oil
taken up in DCM (50 mL). This was washed with satu-
rated NaCl solution (2 · 30 mL) and dried over magne-
sium sulfate prior to filtration and removal of the
solvent in vacuo. The crude product was purified by col-
umn chromatography [DCM > DCM–ethyl acetate
(19:1)] and dried in vacuo (P2O5) to yield the title com-
pound (1.22 g, 82%) as a white crystalline solid. Rf 0.23
[DCM]; Mp 48–50 ꢁC; (Found: C, 76.43%; H, 7.47%; N,
7.67%. C23H26N2O2 requires: C, 76.21%; H, 7.23%; N,
7.73%); dH (400 MHz, CDCl3): 0.83 (6H, t, 2 · N–
CH2–CH3), 1.47 (3H, t, O–CH2–CH3), 2.41 (4H, q,
2 · N–CH2–CH3), 3.76 (2H, s, quinoline–CH2–N), 4.49
(2H, q, O–CH2–CH3), 7.47 (5H, m, 5Ar–H), 7.57 (1H,
t, Ar–Hb or Ar–Hc), 7.71 (1H, t, Ar–Hb or Ar–Hc),
7.88 (1H, d, Ar–Ha or Ar–Hd, Jab or Jdc 8.6 Hz), 8.14
(1H, d, Ar–Ha or Ar–Hd, Jab or Jdc 8.6 Hz); dC
(100 MHz, CDCl3): 10.43, 14.34, 45.59, 53.03, 61.19,
124.08, 124.40, 127.19, 128.27, 128.33, 129.09, 129.29,
129.49, 129.85, 140.08, 140.62, 146.95, 160.49, 168.10;
IR (KBr) mmax 2974, 1732 (ester), 1217, 764; m/z 362
(M+, 10), 333 (100), 287 (50), 262 (50), 216 (55), 86 (50).
5.18. 2-Phenyl-3-pyrazol-1-ylmethylquinoline-4-carbox-
ylic acid ethyl ester (5d)
Using the same method as for the synthesis of amine
(5a), pyrazole (0.36 g, 5.4 · 10ꢁ3 mol) and benzylic bro-
mide (4a) (1.0 g, 2.7 · 10ꢁ3 mol) in toluene (15 mL) were
stirred at room temperature for 24 h. Purification of the
crude product by column chromatography [DCM >
DCM–ethyl acetate (19:1)] and drying in vacuo (P2O5)
gave the title compound (0.97 g, 73%) as a colourless
oil. Rf 0.40 [DCM–ethyl acetate (19:1)]; dH (400 MHz,
CDCl3): 1.35 (3H, t, O–CH2–CH3), 4.44 (2H, q, O–
CH2–CH3), 5.49 (2H, s, quinoline–CH2–N), 6.15 (1H,
t, Ar–Hf), 7.08 (1H, d, Ar–He or Ar–Hg, Jef or Jgf
2.4 Hz), 7.44 (6H, m, 5Ar–H + Ar–He or Ar–Hg), 7.62
(1H, t, Ar–Hb or Ar–Hc), 7.79 (1H, t, Ar–Hb or Ar–
Hc), 7.85 (1H, d, Ar–Ha or Ar–Hd, Jab or Jdc 8.6 Hz),
8.19 (1H, d, Ar–Ha or Ar–Hd, Jab or Jdc 8.6 Hz); IR
(KBr) mmax 3449, 1730 (ester), 1284, 1224, 763; m/z 357
(M+, 10), 284 (100), 260 (35), 216 (35).
5.16. 2-Phenyl-3-piperdin-1-ylmethyl-quinoline-4-carb-
oxylic acid ethyl ester (5b)
Using the same method as for the synthesis of amine
(5a), piperidine (0.69 g, 8.1 · 10ꢁ3 mol) and benzylic
bromide (4a) (1.5 g, 4.05 · 10ꢁ3 mol) in toluene
(20 mL) were stirred at room temperature for 24 h. Puri-
fication of the crude product by column chromatogra-
phy [DCM > DCM–ethyl acetate (19:1)] and drying in
vacuo (P2O5) gave the title compound (1.35 g, 88%) as
a white solid. Rf 0.19 [DCM]; Mp 110–112 ꢁC; (Found:
C, 76.69%; H, 7.26%; N, 7.29%. C24H26N2O2 requires:
C, 76.98%; H, 7.00%; N, 7.48%); dH (400 MHz, CDCl3):
1.34 (2H, s, N–(CH2–CH2)2–CH2), 1.45 (4H, quintet,
2 · N–CH2–CH2), 1.48 (3H, t, O–CH2–CH3), 2.24
(4H, s (broad), 2 · N–CH2–CH2), 3.64 (2H, s, quino-
line–CH2–N), 4.53 (2H, q, O–CH2–CH3), 7.47 (5H, m,
5Ar–H), 7.57 (1H, t, Ar–Hb or Ar–Hc), 7.71 (1H, t,
Ar–Hb or Ar–Hc), 7.92 (1H, d, Ar–Ha or Ar–Hd, Jab
or Jdc 8.6 Hz), 8.14 (1H, d, Ar–Ha or Ar–Hd, Jab or
Jdc 8.6 Hz); IR (KBr) mmax 2937, 1727 (ester), 1214,
1177, 765; m/z 374 (M+, 30), 345 (100), 289 (50), 260
(70), 216 (100).
5.19. 6-Diethylaminomethyl-2-phenyl-quinoline-4-carb-
oxylic acid ethyl ester (5e)
Using the same method as for the synthesis of amine
(5a), diethylamine (0.32 g, 4.32 · 10ꢁ3 mol) and benzylic
bromide (4b) (0.8 g, 2.16 · 10ꢁ3 mol) in toluene (15 mL)
were stirred at room temperature for 24 h. Purification
of the crude product by column chromatography [hex-
ane > hexane–ethyl acetate (3:1)] and drying in vacuo
(P2O5) gave the title compound (0.6 g, 77%) as a white
solid. Rf 0.19 [hexane–ethyl acetate (3:1)]; Mp 63–
65 ꢁC; (Found: C, 76.08%; H, 7.47%; N, 7.69%.
C23H26N2O2 requires: C, 76.21%; H, 7.23%; N,
7.73%); dH (400 MHz, CDCl3): 1.09 (6H, t, 2 · N–
CH2–CH3), 1.51 (3H, t, O–CH2–CH3), 2.59 (4H, q,
2 · N–CH2–CH3), 3.78 (2H, s, quinoline–CH2–N), 4.55

A. N. Boa et al. / Bioorg. Med. Chem. 13 (2005) 1945–1967
1955
(2H, q, O–CH2–CH3), 7.51 (3H, m, 3Ar–H), 7.84 (1H,
dd, Ar–Hc, Jcb 2.0 Hz, Jcd 8.8 Hz), 8.18 (3H, m, 2Ar–
H + Ar–Hd), 8.36 (1H, s, Ar–Ha), 8.62 (1H, d, Ar–Hb,
Jbc 2.0 Hz); IR (KBr) mmax 2974, 2971, 1725 (ester),
1244, 1152, 1035; m/z 362 (M+, 10), 347 (20), 290
(100), 262 (40), 217 (15).
vacuo (P2O5) gave the title compound (0.97 g, 73%) as
a white solid. Rf 0.15 [hexane–ethyl acetate (3:1)]; Mp
70–72 ꢁC; dH (400 MHz, CDCl3): 1.48 (3H, t, O–CH2–
CH3), 4.53 (2H, q, O–CH2–CH3), 5.56 (2H, s, quino-
line–CH2–N), 6.34 (1H, t, Ar–Hc), 7.54 (6H, m, 6Ar–
H), 8.19 (3H, m, 3Ar–H), 8.40 (1H, s, Ar–Ha), 8.62
(1H, d, Ar–Hb); IR (KBr) mmax 3399, 1712 (ester),
1246, 1143, 755; m/z 357 (M+, 100), 328 (70), 290 (50),
262 (40), 216 (25).
5.20. 2-Phenyl-6-piperdin-1-ylmethyl-quinoline-4-carb-
oxylic acid ethyl ester (5f)
Using the same method as for the synthesis of amine
(5a), piperidine (0.37 g, 4.32 · 10ꢁ3 mol) and benzylic
bromide (4b) (0.8 g, 2.16 · 10ꢁ3 mol) in toluene
(15 mL) were stirred at room temperature for 24 h. Puri-
fication of the crude product by column chromatogra-
phy [hexane > hexane–ethyl acetate (1:1)] and drying
in vacuo (P2O5) gave the title compound (0.65 g, 80%)
as a white solid. Rf 0.21 [hexane–ethyl acetate (3:1)];
Mp 93–95 ꢁC; (Found: C, 76.69%; H, 7.23%; N,
7.47%. C24H26N2O2 requires: C, 76.98%; H, 7.00%; N,
7.48%); dH (400 MHz, CDCl3): 1.46 (2H, m, N–(CH2–
CH2)2–CH2), 1.51 (3H, t, O–CH2–CH3), 1.60 (4H, quin-
tet, 2 · N–CH2–CH2), 2.45 (4H, s (broad), 2 · N–CH2–
CH2), 3.68 (2H, s, quinoline–CH2–N), 4.55 (2H, q, O–
CH2–CH3), 7.51 (3H, m, 3Ar–H), 7.82 (1H, dd, Ar–
Hc, Jcb 1.7 Hz, Jcd 8.5 Hz), 8.18 (3H, m, 2Ar–H + Ar–
Hd), 8.36 (1H, s, Ar–Ha), 8.60 (1H, d, Ar–Hb, Jbc
1.7 Hz); IR (KBr) mmax 2930, 1715 (ester), 1230, 1153,
1037, 696; m/z 374 (M+, 15), 291 (100), 262 (80), 245
(20), 217 (25).
5.23. 8-Diethylaminomethyl-2-phenyl-quinoline-4-carb-
oxylic acid ethyl ester (5i)
Using the same method as for the synthesis of amine
(5a), diethylamine (0.20 g, 2.7 · 10ꢁ3 mol) and benzylic
bromide (4c) (0.5 g, 1.35 · 10ꢁ3 mol) in toluene
(10 mL) were stirred at room temperature for 24 h. Puri-
fication of the crude product by column chromatogra-
phy [hexane–ethyl acetate (3:1) > (1:2)] and drying in
vacuo (P2O5) gave the title compound (0.41 g, 84%) as
a pale yellow oil. Rf 0.22 [hexane–ethyl acetate (3:1)];
dH (400 MHz, CDCl3): 1.12 (6H, t, 2 · N–CH2–CH3),
1.50 (3H, t, O–CH2–CH3), 2.69 (4H, q, 2 · N–CH2–
CH3), 4.43 (2H, s, quinoline–CH2–N), 4.54 (2H, q, O–
CH2–CH3), 7.55 (4H, m, 3Ar–H + Ar–Hc), 7.98 (1H,
d, Ar–Hd, Jdc 7.1 Hz), 8.27 (2H, m, 2Ar–H), 8.37 (1H,
s, Ar–Ha), 8.56 (1H, d, Ar–Hb, Jbc 7.3 Hz); IR (KBr)
mmax 2976, 1730 (ester), 1241, 1201, 1097, 770; m/z 362
(M+), 333 (20), 291 (100), 262 (40).
5.24. 2-Phenyl-8-piperdin-1-ylmethyl-quinoline-4-carb-
oxylic acid ethyl ester (5j)
5.21. 6-Morpholin-4-ylmethyl-2-phenyl-quinoline-4-carb-
oxylic acid ethyl ester (5g)
Using the same method as for the synthesis of amine
(5a), piperidine (0.23 g, 2.7 · 10ꢁ3 mol) and benzylic
bromide (4c) (0.5 g, 1.35 · 10ꢁ3 mol) in toluene
(15 mL) were stirred at room temperature for 24 h.
Purification of the crude product by column chroma-
tography [hexane–ethyl acetate (3:1) > (1:1)] and drying
in vacuo (P2O5) gave the title compound (0.41 g, 80%)
as a pale yellow oil. Rf 0.22 [hexane–ethyl acetate
(3:1)]; dH (400 MHz, CDCl3): 1.46 (2H, m, N–(CH2–
CH2)2–CH2), 1.50 (3H, t, O–CH2–CH3), 1.64 (4H,
quintet, 2 · N–CH2–CH2), 2.59 (4H, s (broad), 2 · N–
CH2–CH2), 4.37 (2H, s, quinoline–CH2–N), 4.54 (2H,
q, O–CH2–CH3), 7.55 (4H, m, 3Ar–H + Ar–Hc), 7.91
(1H, d, Ar–Hd, Jdc 6.1 Hz), 8.28 (2H, m, 2Ar–H),
8.38 (1H, s, Ar–Ha), 8.58 (1H, d, Ar–Hb, Jbc 7.6 Hz);
IR (KBr) mmax 2926, 1723 (ester), 1247, 1195, 1088;
m/z 374 (M+), 345, 331, 303, 291 (100), 263 (30), 218
(15).
Using the same method as for the synthesis of amine
(5a), morpholine (0.38 g, 4.32 · 10ꢁ3 mol) and benzylic
bromide (4b) (0.8 g, 2.16 · 10ꢁ3 mol) in toluene
(15 mL) were stirred at room temperature for 24 h. Puri-
fication of the crude product by column chromatogra-
phy [hexane–ethyl acetate (3:1) > ethyl acetate] and
drying in vacuo (P2O5) gave the title compound (0.7 g,
88%) as a white solid. Rf 0.16 [hexane–ethyl acetate
(3:1)]; Mp 86–88 ꢁC; (Found: C, 73.09%; H, 6.60%; N,
7.39%. C23H24N2O3 requires: C, 73.38%; H, 6.43%; N,
7.44%); dH (400 MHz, CDCl3): 1.51 (3H, t, O–CH2–
CH3), 2.52 (4H, t, 2 · N–CH2–CH2–O), 3.71 (2H, s,
quinoline–CH2–N), 3.74 (4H, t, 2 · N–CH2–CH2–O),
4.55 (2H, q, O–CH2–CH3), 7.51 (3H, m, 3Ar–H), 7.82
(1H, dd, Ar–Hc, Jcb 1.7 Hz, Jcd 8.6 Hz), 8.18 (3H, m,
2Ar–H + Ar–Hd), 8.37 (1H, s, Ar–Ha), 8.64 (1H, d,
Ar–Hb, Jbc 1.7 Hz); IR (KBr) mmax 2821, 1728 (ester),
1240, 1155, 1116; m/z 376 (M+, 15), 291 (100), 262
(70), 245 (30), 217 (20).
5.25. 8-Morpholin-4-ylmethyl-2-phenyl-quinoline-4-car-
boxylic acid ethyl ester (5k)
5.22. 2-Phenyl-6-pyrazol-1-ylmethylquinoline-4-carb-
oxylic acid ethyl ester (5h)
Using the same method as for the synthesis of amine
(5a), morpholine (0.24 g, 2.7 · 10ꢁ3 mol) and benzylic
bromide (4c) (0.5 g, 1.35 · 10ꢁ3 mol) in toluene
(10 mL) were stirred at room temperature for 24 h.
Purification of the crude product by column chroma-
tography [hexane–ethyl acetate (3:1) > (1:2)] and drying
in vacuo (P2O5) gave the title compound (0.41 g, 80%)
as a white solid. Rf 0.15 [hexane–ethyl acetate (3:1)];
Using the same method as for the synthesis of amine
(5a), pyrazole (0.29 g, 4.32 · 10ꢁ3 mol) and benzylic
bromide (4b) (0.8 g, 2.16 · 10ꢁ3 mol) in toluene
(15 mL) were stirred at room temperature for 24 h. Puri-
fication of the crude product by column chromatogra-
phy [hexane–ethyl acetate (3:1) > (1:1)] and drying in

1956
A. N. Boa et al. / Bioorg. Med. Chem. 13 (2005) 1945–1967
Mp 69–71 ꢁC; dH (400 MHz, CDCl3): 1.51 (3H, t, O–
CH2–CH3), 2.66 (4H, t, 2 · N–CH2–CH2–O), 3.77
(4H, t, 2 · N–CH2–CH2–O), 4.40 (2H, s, quinoline–
CH2–N), 4.55 (2H, q, O–CH2–CH3), 7.54 (4H, m,
3Ar–H + Ar–Hc), 7.91 (1H, dd, Ar–Hd, Jdc 7.1 Hz,
Jdb 1.3 Hz), 8.27 (2H, m, 2Ar–H), 8.39 (1H, s, Ar–
Ha), 8.61 (1H, dd, Ar–Hb, Jbc 8.6 Hz, Jbd 1.3 Hz); IR
(KBr) mmax 3436, 1720 (ester), 1231, 1197, 1114, 1092,
769; m/z 376 (M+), 347, 291 (100), 275 (15), 263 (50),
218 (20).
5.28. 6-(4-Bromophenoxymethyl)-2-phenyl-quinoline-4-
carboxylic acid ethyl ester (6b)
Using the same method as for the synthesis of ether (6a),
benzylic bromide (4b) (0.5 g, 1.35 · 10ꢁ3 mol) gave the
title compound (0.5 g, 81%) as a white solid. Rf 0.62
[hexane–ethyl acetate (3:1)]; Mp 131–133 ꢁC; (Found:
C, 64.68%; H, 4.44%; N, 3.16%. C25H20NO3Br requires:
C, 64.95%; H, 4.36%; N, 3.03%); dH (400 MHz, CDCl3):
1.50 (3H, t, O–CH2–CH3), 4.54 (2H, q, O–CH2–CH3),
5.26 (2H, s, quinoline–CH2–N), 6.92 (2H, d, Ar–Hf,
Jfe 9.3 Hz), 7.40 (2H, d, Ar–He, Jef 9.3 Hz), 7.54 (3H,
m, 3Ar–H), 7.83 (1H, dd, Ar–Hc, Jcb 2.0 Hz, Jcd
8.7 Hz), 8.21 (2H, m, 2Ar–H), 8.25 (1H, d, Ar–Hd, Jdc
8.7 Hz), 8.42 (1H, s, Ar–Ha), 8.81 (1H, d, Ar–Hb, Jbc
2.0 Hz); dC (100 MHz, CDCl3): 14.48, 62.09, 70.39,
113.52, 116.93, 120.69, 123.99, 124.01, 127.62, 129.08,
129.18, 129.94, 130.95, 132.50, 135.96, 136.28, 138.85,
149.18, 157.10, 157.89, 166.41; IR (KBr) mmax 1724 (es-
ter), 1484, 1229 (ether), 1170, 1145, 821; m/z 463
(M+), 461 (M+), 290 (100), 262 (25), 217 (10).
5.26. 2-Phenyl-8-pyrazol-1-ylmethylquinoline-4-carb-
oxylic acid ethyl ester (5l)
Using the same method as for the synthesis of amine
(5a), pyrazole (0.18 g, 2.7 · 10ꢁ3 mol) and benzylic bro-
mide (4c) (0.8 g, 1.35 · 10ꢁ3 mol) in toluene (10 mL)
were stirred at room temperature for 24 h. Purification
of the crude product by column chromatography
[DCM > DCM–ethyl acetate (19:1)] and drying in vacuo
(P2O5) gave the title compound (0.39 g, 81%) as a white
solid. Rf 0.31 [DCM]; Mp 128–130 ꢁC; (Found: C,
73.69%; H, 5.41%; N, 11.72%. C22H19N3O2 requires:
C, 73.93%; H, 5.36%; N, 11.76%); dH (400 MHz,
CDCl3): 1.50 (3H, t, O–CH2–CH3), 4.54 (2H, q, O–
CH2–CH3), 6.17 (2H, s, quinoline–CH2–N), 6.26 (1H,
t, Ar–He), 7.42 (1H, dd, Ar–Hd, Jdc 7.1 Hz, Jdb
1.2 Hz), 7.55 (6H, m, 5Ar–H + Ar–Hc), 8.27 (2H, m,
2Ar–H), 8.44 (1H, s, Ar–Ha), 8.67 (1H, dd, Ar–Hb,
Jbc 8.6 Hz, Jbd 1.2 Hz); IR (KBr) mmax 3428, 2978, 1722
(ester), 1247, 1200, 760; m/z 357 (M+, 50), 356 (50),
328 (100), 277 (10), 249 (15), 204 (15).
5.29. 8-(4-Bromophenoxymethyl)-2-phenyl-quinoline-4-
carboxylic acid ethyl ester (6c)
Using the same method as for the synthesis of ether (6a),
benzylic bromide (4c) (0.5 g, 1.35 · 10ꢁ3 mol) gave the
title compound (0.5 g, 81%) as a white solid. Rf 0.74
[hexane–ethyl acetate (3:1)]; Mp 99–100 ꢁC; (Found: C,
64.65%; H, 4.47%; N, 3.23%. C25H20NO3Br requires:
C, 64.95%; H, 4.36%; N, 3.03%); dH (400 MHz, CDCl3):
1.51 (3H, t, O–CH2–CH3), 4.56 (2H, q, O–CH2–CH3),
5.93 (2H, s, quinoline–CH2–N), 6.97 (2H, d, Ar–Hf,
Jfe 9 Hz), 7.30 (2H, d, Ar–He, Jef 9 Hz), 7.54 (3H, m,
3Ar–H), 7.62 (1H, dd, Ar–Hc, Jcb 8.4 Hz, Jcd 7.0 Hz),
7.90 (1H, d, Ar–Hd, Jdc 7.0 Hz), 8.22 (2H, m, 2Ar–H),
8.44 (1H, s, Ar–Ha), 8.68 (1H, d, Ar–Hb, Jbc 8.7 Hz);
dC (100 MHz, CDCl3): 14.44, 61.99, 66.85, 113.03,
116.95, 119.78, 123.81, 125.01, 127.42, 127.51, 127.79,
128.95, 129.94, 132.34, 135.44, 136.42, 138.58, 146.32,
155.35, 158.22, 166.37; IR (KBr) mmax 1712 (ester),
1491, 1342, 1251, 1232 (ether), 818, 770; m/z 463 (M+,
5), 461 (M+, 5), 290 (100), 262 (25), 217 (10).
5.27. 3-(4-Bromophenoxymethyl)-2-phenyl-quinoline-4-
carboxylic acid ethyl ester (6a)
Benzylic bromide (4b) (0.5 g, 1.35 · 10ꢁ3 mol), 4-bromo-
phenol (0.26 g, 1.49 · 10ꢁ3 mol) and potassium carbon-
ate (0.41 g, 2.97 · 10ꢁ3 mol) in DMF (10 mL) were
stirred at room temperature for 24 h. Water (50 mL)
was added and the product extracted into DCM
(2 · 30 mL). The organic layer was washed with satu-
rated NaCl solution (2 · 30 mL) and dried over magne-
sium sulfate prior to filtration and removal of the
solvent in vacuo. The crude product was purified by col-
umn chromatography [hexane–ethyl acetate (3:1)] and
dried in vacuo (P2O5) to yield the title compound
(0.5 g, 81%) as a white solid. Rf 0.51 [hexane–ethyl ace-
tate (3:1)]; Mp 122–124 ꢁC; (Found: C, 64.73%; H,
4.38%; N, 2.69%. C25H20NO3Br requires: C, 64.95%;
H, 4.36%; N, 3.03%); dH (400 MHz, CDCl3): 1.33 (3H,
t, O–CH2–CH3), 4.44 (2H, q, O–CH2–CH3), 5.17 (2H,
s, quinoline–CH2–N), 6.71 (2H, d, Ar–Hf, Jfe 8.8 Hz),
7.34 (2H, d, Ar–He, Jef 8.8 Hz), 7.49 (3H, m, 3Ar–H),
7.63 (3H, m, 2Ar–H + Ar–Hb or Ar–Hc), 7.79 (1H, t,
Ar–Hb or Ar–Hc), 7.93 (1H, d, Ar–Ha or Ar–Hd, Jab
or Jdc 9.1 Hz), 8.20 (1H, d, Ar–Ha or Ar–Hd, Jab or
Jdc 8.6 Hz); dC (100 MHz, CDCl3): 14.27, 62.29, 65.66,
113.79, 116.48, 123.49, 124.36, 124.83, 127.82, 128.66,
129.06, 129.18, 129.99, 130.67, 132.41, 139.45, 141.02,
147.79, 157.24, 159.70, 167.18; IR (KBr) mmax 1728 (es-
ter), 1487, 1474, 1231 (ether), 819; m/z 463 (M+), 461
(M+), 290 (100), 262 (85), 217 (45).
5.30. 3-(4-Bromophenylsulfanylmethyl)-2-phenyl-quino-
line-4-carboxylic acid ethyl ester (7a)
Triethylamine (0.27 g, 2.7 · 10ꢁ3 mol) was added to
benzylic bromide (4a) (0.5 g, 1.3510ꢁ3 mol) dissolved
in THF (10 mL) and cooled to 0 ꢁC before the addition
of 4-bromothiophenol (0.25 g, 1.35 · 10ꢁ3 mol). The
reaction was stirred at room temperature for 2 h and
diethyl ether (20 mL) added. The organic layer was
washed with water (15 mL), saturated NaCl solution
(15 mL) and dried over magnesium sulfate prior to fil-
tration and removal of the solvent in vacuo. The crude
product was triturated with diethyl ether and then dried
in vacuo to yield the title compound (0.53 g, 82%) as a
white solid. Rf 0.48 [hexane–ethyl acetate (3:1)]; Mp
108–110 ꢁC; (Found: C, 62.96%; H, 4.27%; N, 3.09%;
S, 6.54%. C25H20NO2SBr requires: C, 62.76%; H,
4.21%; N, 2.93%; S, 6.70%); dH (400 MHz, CDCl3):
1.47 (3H, t, O–CH2–CH3), 4.35 (2H, s, quinoline–

A. N. Boa et al. / Bioorg. Med. Chem. 13 (2005) 1945–1967
1957
CH2–N), 4.56 (2H, q, O–CH2–CH3), 6.97 (2H, d, Ar–
Hf, Jfe 8.4 Hz), 7.29 (2H, d, Ar–He, Jef 8.4 Hz), 7.46
(3H, m, 3Ar–H), 7.52 (2H, m, 2Ar–H), 7.62 (1H, t,
Ar–Hb or Ar–Hc), 7.75 (1H, t, Ar–Hb or Ar–Hc), 7.89
(1H, d, Ar–Ha or Ar–Hd, Jab or Jdc 8.4 Hz), 8.16 (1H,
d, Ar–Ha or Ar–Hd, Jab or Jdc 8.4 Hz); dC (100 MHz,
CDCl3): 14.34, 34.78, 62.39, 121.23, 123.59, 124.73,
125.77, 127.75, 128.48, 128.72, 128.98, 130.00, 130.23,
132.04, 132.43, 134.75, 139.74, 140.17, 147.07, 160.49,
167.31; IR (KBr) mmax 1728 (ester), 1476, 1221, 1092,
1007, 701; m/z 479 (M+, 35), 477 (35), 290 (80), 262
(100), 216 (60).
(5 mL) and water (2.5 mL) at room temperature for
2 h, then the reaction solvent was removed in vacuo.
The resulting solid was filtered, washed with diethyl
ether (10 mL) and dried in vacuo (P2O5) to yield the
title compound (0.20 g, 81%) as a white solid. dH
(400 MHz, DMSO): 2.14 (4H, t, 2 · N–CH2–CH2–O),
3.28 (4H, t, 2 · N–CH2–CH2–O), 3.47 (2H, s, quino-
line–CH2–N), 7.39 (3H, m, 3Ar–H), 7.46 (1H, t, Ar–
Hb or Ar–Hc), 7.59 (2H, m, 2Ar–H), 7.62 (1H, t,
Ar–Hb or Ar–Hc), 7.84 (1H, d, Ar–Ha or Ar–Hd,
Jab or Jdc 8.3 Hz), 7.94 (1H, d, Ar–Ha or Ar–Hd, Jab
or Jdc 8.3 Hz).
5.31. 6-(4-Bromo-phenylsulfanylmethyl)-2-phenyl-quino-
line-4-carboxylic acid ethyl ester (7b)
5.34. Sodium 2-phenyl-3-pyrazol-1-ylmethylquinoline-4-
carboxylate (8d)
Using the same method as for the synthesis of thioether
(7a), benzylic bromide (4b) (0.5 g, 1.35 · 10ꢁ3 mol) gave
the title compound (0.55 g, 85%) as a white solid. Rf 0.31
[hexane–DCM (2:1)]; Mp 138–140 ꢁC; (Found: C,
62.82%; H, 4.12%; N, 2.96%; S, 6.59%. C25H20NO2SBr
requires: C, 62.76%; H, 4.21%; N, 2.93%; S, 6.70%);
dH (400 MHz, CDCl3): 1.49 (3H, t, O–CH2–CH3), 4.28
(2H, s, quinoline–CH2–N), 4.52 (2H, q, O–CH2–CH3),
7.18 (2H, d, Ar–Hf, Jfe 8.4 Hz), 7.35 (2H, d, Ar–He,
Jef 8.4 Hz), 7.53 (3H, m, 3Ar–H), 7.74 (1H, dd, Ar–
Hc, Jcb 2.0 Hz, Jcd 8.7 Hz), 8.17 (3H, m, 2Ar–H + Ar–
Hd), 8.38 (1H, s, Ar–Ha), 8.57 (1H, d, Ar–Hb, Jbc
2.0 Hz); dC (100 MHz, CDCl3): 14.42, 39.91, 61.97,
120.56, 120.89, 123.88, 125.12, 127.51, 129.00, 129.81,
130.77, 130.90, 132.02, 132.26, 134.81, 135.64, 136.87,
138.82, 148.70, 156.78, 166.27; IR (KBr) mmax 1725 (es-
ter), 1252, 1146, 1088; m/z 479 (M+, 10), 477 (M+,
10), 290 (100), 262 (30).
Using the same method as for the synthesis of carboxyl-
ate salt (8c), ester (5d) (0.49g, 1.37 · 10ꢁ3 mol) gave the
title product (0.35 g, 73%) was obtained as a white solid.
d
H (400 MHz, DMSO): 5.47 (2H, s, quinoline–CH2–N),
6.10 (1H, t, Ar–Hf), 7.25 (1H, d, Ar–He or Ar–Hg, Jef or
Jgf 2.2 Hz), 7.32 (1H, d, Ar–He or Ar–Hg, Jef or Jgf
2.2 Hz), 7.44 (5H, m, 5Ar–H), 7.76 (1H, t, Ar–Hb or
Ar–Hc), 7.91 (1H, t, Ar–Hb or Ar–Hc), 7.94 (1H, d,
Ar–Ha or Ar–Hd, Jab or Jdc 8.3 Hz), 8.12 (1H, d, Ar–
Ha or Ar–Hd, Jab or Jdc 8.3 Hz).
5.35. Sodium 6-diethylaminomethyl-2-phenyl-quinoline-4-
carboxylate (8e)
Using the same method as for the synthesis of carboxyl-
ate salt (8c), ester (5e) (0.25 g, 6.9 · 10ꢁ4 mol) gave the
title product (0.2 g, 83%) was obtained as a pale yellow
solid. dH (400 MHz, DMSO): 0.99 (6H, t, 2 · N–CH2–
CH3), 2.49 (4H, q, 2 · N–CH2–CH3), 3.65 (2H, s, quin-
oline–CH2–N), 7.49 (3H, m, 3Ar–H), 7.65 (1H, dd, Ar–
Hc, Jcb 1.9 Hz, Jcd 8.7 Hz), 7.93 (1H, d, Ar–Hd, Jdc
8.7 Hz), 7.99 (1H, s, Ar–Ha), 8.19 (2H, m, 2Ar–H),
8.54 (1H, d, Ar–Hb, Jbc 1.9 Hz).
5.32. 8-(4-Bromo-phenylsulfanylmethyl)-2-phenyl-quino-
line-4-carboxylic acid ethyl ester (7c)
Using the same method as for the synthesis of thioether
(7a), benzylic bromide (4c) (0.5 g, 1.35 · 10ꢁ3 mol) gave
the title compound (0.55 g, 85%) as a white solid. Rf
0.74 [hexane–ethyl acetate (3:1)]; Mp 105–107 ꢁC;
(Found: C, 62.82%; H, 4.13%; N, 3.09%; S, 6.54%.
C25H20NO2SBr requires: C, 62.76%; H, 4.21%; N,
2.93%; S, 6.70%); dH (400 MHz, CDCl3): 1.50 (3H, t,
O–CH2–CH3), 4.55 (2H, q, O–CH2–CH3), 4.90 (2H, s,
quinoline–CH2–N), 7.21 (2H, d, Ar–Hf, Jfe 8.6 Hz),
7.30 (2H, d, Ar–He, Jef 8.4 Hz), 7.53 (4H, m, 3Ar–
H + Ar–Hc), 7.67 (1H, d, Ar–Hd, Jdc 7.3 Hz), 8.24
(2H, m, 2Ar–H), 8.42 (1H, s, Ar–Ha), 8.63 (1H, dd,
Ar–Hb, Jbc 8.7 Hz, Jbd 1.4 Hz); dC (100 MHz, CDCl3):
14.47, 35.27, 62.05, 119.85, 120.21, 124.27, 125.11,
127.37, 127.57, 129.00, 129.88, 129.95, 131.81, 131.83,
136.46, 136.70, 136.77, 138.76, 147.00, 155.39, 166.55;
IR (KBr) mmax 1723 (ester), 1474, 1245, 1206, 1092,
770; m/z 479 (M+, 60), 477 (M+, 60), 446 (10), 444
(10), 290 (100), 262 (60).
5.36. Sodium 2-phenyl-6-piperdin-1-ylmethyl-quinoline-4-
carboxylate (8f)
Using the same method as for the synthesis of carboxyl-
ate salt (8c), ester (5f) (0.34 g, 9.08 · 10ꢁ4 mol) gave the
title product (0.3 g, 90%) was obtained as a white solid.
dH (400 MHz, DMSO): 1.39 (2H, m (broad), N–(CH2–
CH2)2–CH2), 1.50 (4H, quintet, 2 · N–CH2–CH2), 2.35
(4H, s (broad), 2 · N–CH2–CH2), 3.55 (2H, s, quino-
line–CH2–N), 7.49 (3H, m, 3Ar–H), 7.63 (1H, dd, Ar–
Hc, Jcb 2.0 Hz, Jcd 8.7 Hz), 7.93 (1H, d, Ar–Hd, Jdc
8.7 Hz), 7.98 (1H, s, Ar–Ha), 8.19 (2H, m, 2Ar–H),
8.52 (1H, d, Ar–Hb, Jbc 2.0 Hz).
5.37. Sodium 6-morpholin-4-ylmethyl-2-phenyl-quinoline-
4-carboxylate (8g)
Using the same method as for the synthesis of carboxyl-
ate salt (8c), ester (5g) (0.25 g, 6.64 · 10ꢁ4 mol) gave the
title product (0.2 g, 83%) was obtained as a white solid.
dH (400 MHz, DMSO): 2.39 (4H, t (broad), 2 · N–CH2–
CH2–O), 3.58 (4H, t, 2 · N–CH2–CH2–O), 3.59 (2H, s,
quinoline–CH2–N), 7.49 (3H, m, 3Ar–H), 7.65 (1H,
5.33. Sodium 3-morpholin-4-ylmethyl-2-phenyl-quinoline-
4-carboxylate (8c)
Ester (5c) (0.25 g, 6.64 · 10ꢁ4 mol) and sodium hydr-
oxide (0.027 g, 6.64 · 10ꢁ4 mol) were stirred in dioxane

1958
A. N. Boa et al. / Bioorg. Med. Chem. 13 (2005) 1945–1967
dd, Ar–Hc, Jcb 2.0 Hz, Jcd 8.7 Hz), 7.94 (1H, d, Ar–Hd,
Jdc 8.7 Hz), 7.99 (1H, s, Ar–Ha), 8.19 (2H, m, Ar–H),
8.56 (1H, d, Ar–Hb, Jbc 2.0 Hz).
5.43. 2-Ethyl-4-phenyl-2,3-dihydropyrrolo[3,4-c]quinolin-
1-one (9a)
Using the same method as for the synthesis of amine
(5a), ethylamine (0.24 g, 5.4 · 10ꢁ3 mol) and benzylic
bromide (4a) (1.0 g, 2.7 · 10ꢁ3 mol) in toluene (30 mL)
were stirred at room temperature for 24 h. Purification
of the crude product by column chromatography
[DCM > DCM–ethyl acetate (19:1)] and drying in vacuo
(P2O5) gave the title compound (0.7 g, 90%) as a white
solid. Rf 0.47 [DCM–ethyl acetate (19:1)]; Mp 149–
151 ꢁC; (Found: C, 79.05%; H, 5.89%; N, 9.44%.
C19H16N2O requires: C, 79.14%; H, 5.59%; N, 9.72%);
dH (400 MHz, CDCl3): 1.35 (3H, t, CH2–CH3), 3.79
(2H, t, N–CH2–CH3), 4.68 (2H, s, quinoline–CH2–N),
7.54 (3H, m, 3Ar–H), 7.70 (1H, t, Ar–Hb or Ar–Hc),
7.81 (1H, t, Ar–Hb or Ar–Hc), 7.91 (2H, m, 2Ar–H),
8.26 (1H, d, Ar–Ha or Ar–Hd, Jab or Jdc 8.5 Hz), 9.17
(1H, d, Ar–Ha or Ar–Hd, Jab or Jdc 8.3 Hz); dC
(100 MHz, CDCl3): 13.76, 37.21, 49.47, 122.79, 123.58,
127.92, 128.28, 128.96, 129.53, 129.56, 130.02, 133.23,
136.25, 138.57, 148.33, 153.53, 167.70; IR (KBr) mmax
1695 (amide), 1458, 1250, 776, 707; m/z 288 (M+, 100),
273 (20), 259 (45), 216, (40), 108 (30).
5.38. Sodium 2-phenyl-6-pyrazol-1-ylmethylquinoline-4-
carboxylate (8h)
Using the same method as for the synthesis of carboxyl-
ate salt (8c), ester (5h) (0.25 g, 6.64 · 10ꢁ4 mol) gave the
title product (0.2 g, 83%) was obtained as a white solid.
d
H (400 MHz, DMSO): 5.48 (2H, s, quinoline–CH2–N),
6.27 (1H, t, Ar–Hc), 7.49 (5H, m, 5Ar–H), 7.85 (1H, d,
Ar–H), 7.92 (1H, d, Ar–H), 7.99 (1H, s, Ar–Ha), 8.19
(2H, m, 2Ar–H), 8.64 (1H, d, Ar–Hb).
5.39. Sodium 8-diethylaminomethyl-2-phenyl-quinoline-4-
carboxylate (8i)
Using the same method as for the synthesis of carboxyl-
ate salt (8c), ester (5i) (0.28 g, 7.73 · 10ꢁ4 mol) gave the
title product (0.23 g, 83%) was obtained as a white solid.
dH (400 MHz, DMSO): 1.03 (6H, t, 2 · N–CH2–CH3),
2.58 (4H, q, 2 · N–CH2–CH3), 4.29 (2H, s, quinoline–
CH2–N), 7.49 (4H, m, 3Ar–H + Ar–Hc), 7.77 (1H, d,
Ar–Hd, Jdc 6.4 Hz), 8.01 (1H, s, Ar–Ha), 8.24 (2H, m,
2Ar–H), 8.52 (1H, d, Ar–Hb, Jbc 7.6 Hz).
5.44. 2-Propyl-4-phenyl-2,3-dihydropyrrolo[3,4-c]quino-
lin-1-one (9b)
5.40. Sodium 2-phenyl-8-piperdin-1-ylmethyl-quinoline-4-
carboxyate (8j)
Using the same method as for the synthesis of amine
(5a), propylamine (0.32 g, 5.4 · 10ꢁ3 mol) and benzylic
bromide (4a) (1.0 g, 2.710ꢁ3 mol) in toluene (30 mL)
were stirred at room temperature for 24 h. Purification
of the crude product by column chromatography
[DCM > DCM–ethyl acetate (19:1)] and drying in vacuo
(P2O5) gave the title compound (0.7 g, 86%) as a white
solid. Rf 0.49 [DCM–ethyl acetate (19:1)]; Mp 118–
119 ꢁC; (Found: C, 79.31%; H, 6.10%; N, 9.38%.
C20H18N2O requires: C, 79.44%; H, 6.00%; N, 9.27%);
dH (400 MHz, CDCl3): 1.00 (3H, t, CH2–CH3), 1.77
(2H, sextet, CH2–CH2–CH3), 3.69 (2H, t, N–CH2–
CH2), 4.67 (2H, s, quinoline–CH2–N), 7.55 (3H, m,
3Ar–H), 7.70 (1H, t, Ar–Hb or Ar–Hc), 7.81 (1H, t,
Ar–Hb or Ar–Hc), 7.91 (2H, m, 2Ar–H), 8.26 (1H, d,
Ar–Ha or Ar–Hd, Jab or Jdc 8.3 Hz), 9.17 (1H, d, Ar–
Ha or Ar–Hd, Jab or Jdc 8.3 Hz); IR (KBr) mmax 1693
(amide), 1458, 1247, 779, 705; m/z 302 (M+, 60), 273
(100), 216 (80), 122 (20).
Using the same method as for the synthesis of carboxyl-
ate salt (8c), ester (5j) (0.37 g, 9.88 · 10ꢁ4 mol) gave the
title product (0.31 g, 85%) was obtained as a white solid.
dH (400 MHz, DMSO): 1.40 (2H, m, N–(CH2–CH2)2–
CH2), 1.53 (4H, quintet, 2 · N–CH2–CH2), 3.55 (4H,
s, 2 · N–CH2–CH2), 4.20 (2H, s, quinoline–CH2–N),
7.49 (4H, m, 3Ar–H + Ar–Hc), 7.70 (1H, d, Ar–Hd,
Jdc 6.6 Hz), 7.99 (1H, s, Ar–Ha), 8.24 (2H, m, 2Ar–H),
8.52 (1H, d, Ar–Hb, Jbc 8.6 Hz).
5.41. Sodium 8-morpholin-4-ylmethyl-2-phenyl-quinoline-
4-carboxylate (8k)
Using the same method as for the synthesis of carbox-
ylate salt (8c), ester (5k) (0.25 g, 6.64 · 10ꢁ4 mol) gave
the title product (0.21 g, 85%) was obtained as a white
solid. dH (400 MHz, DMSO): 2.52 (4H, t, 2 · N–
CH2–CH2–O), 3.60 (4H, t, 2 · N–CH2–CH2–O), 4.24
(2H, s, quinoline–CH2–N), 7.49 (4H, m, 3Ar–H + Ar–
Hc), 7.72 (1H, d, Ar–Hd, Jdc 6.1 Hz), 7.98 (1H, s,
Ar–Ha), 8.25 (2H, m, 2Ar–H), 8.53 (1H, d, Ar–Hb,
Jbc 7.0 Hz).
5.45. 2-Butyl-4-phenyl-2,3-dihydropyrrolo[3,4-c]quinolin-
1-one (9c)
Using the same method as for the synthesis of amine (5a),
n-butylamine (0.4 g, 5.4 · 10ꢁ3 mol) and benzylic bro-
mide (4a) (1.0 g, 2.710ꢁ3 mol) in toluene (30 mL) were
stirred at room temperature for 24 h. Purification of the
crude product by column chromatography [DCM >
DCM–ethyl acetate (19:1)] and drying in vacuo (P2O5)
gave the title compound (0.7 g, 82%) as a white solid. Rf
0.57 [DCM–ethyl acetate (19:1)]; Mp 120–122 ꢁC;
(Found: C, 79.54%; H, 6.58%; N, 8.87%. C21H20N2O re-
quires: C, 79.72%; H, 6.37%; N, 8.86%); dH (400 MHz,
CDCl3): 0.98 (3H, t, CH2–CH3), 1.43 (2H, sextet, CH2–
CH2–CH3), 1.72 (2H, quintet, N–CH2–CH2), 3.73 (2H,
5.42. Sodium 2-phenyl-8-pyrazol-1-ylmethylquinoline-4-
carboxylate (8l)
Using the same method as for the synthesis of carboxyl-
ate salt (8c), ester (5l) (0.28 g, 7.83 · 10ꢁ4 mol) gave the
title product (0.24 g, 87%) was obtained as a white solid.
d
H (400 MHz, DMSO): 6.04 (2H, s, quinoline–CH2–N),
6.25 (1H, t, Ar–H), 7.15 (1H, d, Ar–H), 7.47 (5H, m,
5Ar–H), 7.85 (1H, s, Ar–H), 8.04 (1H, s, Ar–Ha), 8.29
(2H, d, 2Ar–H), 8.60 (1H, d, Ar–H).

A. N. Boa et al. / Bioorg. Med. Chem. 13 (2005) 1945–1967
1959
t, N–CH2–CH2), 4.67 (2H, s, quinoline–CH2–N), 7.55
(3H, m, 3Ar–H), 7.70 (1H, t, Ar–Hb or Ar–Hc), 7.81
(1H, t, Ar–Hb or Ar–Hc), 7.91 (2H, m, 2Ar–H), 8.26
(1H, d, Ar–Ha or Ar–Hd, Jab or Jdc 8.5 Hz), 9.17 (1H,
d, Ar–Ha or Ar–Hd, Jab or Jdc 8.3 Hz); dC (100 MHz,
CDCl3): 13.80, 20.20, 30.72, 42.30, 50.12, 122.81,
123.62, 127.91, 128.32, 128.95, 129.54, 129.60, 130.00,
133.27, 136.16, 138.60, 148.34, 153.42, 167.93; IR (KBr)
mmax 2933, 1694 (amide), 1460, 1235, 777, 688; m/z 316
(M+, 100), 273 (80), 216 (60), 122 (15).
(0.546 g, 2.38 · 10ꢁ2 mol) in ethanol (25 mL) and benz-
ylic bromide (4b) (8.0 g, 2.16 · 10ꢁ2 mol) in ethanol
(60 mL) were warmed in a N2 atmosphere for 3 h. The
crude product that crystallised was filtered, washed with
cold ethanol and dried in vacuo (P2O5) to yield the title
compound (4.8 g, 73%) as fine yellow needles. Rf 0.55
[hexane–ethyl acetate (3:1)]; Mp 107–108 ꢁC; (Found:
C, 74.45%; H, 5.09%; N, 4.68%. C19H15NO3 requires:
C, 74.74%; H, 4.95%; N, 4.59%); dH (400 MHz, CDCl3):
1.54 (3H, t, O–CH2CH3), 4.59 (2H, q, O–CH2–CH3),
7.56 (3H, m, 3Ar–H), 8.28 (4H, m, 2Ar–H + Ar–
Hc + Ar–Hd), 8.52 (1H, s, Ar–Ha), 9.35 (1H, d, Ar–
Hb, Jbc 1.7 Hz), 10.23 (1H, s, CHO); dC (100 MHz,
CDCl3): 14.40, 62.35, 121.14, 123.72, 126.64, 127.73,
129.12, 130.55, 131.54, 132.44, 135.10, 136.84, 138.15,
151.87, 159.40, 165.75, 191.89; IR (KBr) mmax 1723 (es-
ter), 1695 (aldehyde), 1588, 1251, 1146; m/z 305 (M+,
75), 276 (10), 233 (100), 204 (35), 176 (10), 102 (25).
5.46. 2-tert-Butyl-4-phenyl-2,3-dihydropyrrolo[3,4-c]-
quinolin-1-one (9d)
Using the same method as for the synthesis of amine
(5a), tert-butylamine (0.4 g, 5.4 · 10ꢁ3 mol) and benzylic
bromide (4a) (1.0 g, 2.7 · 10ꢁ3 mol) in toluene (30 mL)
were stirred at room temperature for 24 h. Purification
of the crude product by column chromatography
[DCM > DCM–ethyl acetate (19:1)] and drying in vacuo
(P2O5) gave the title compound (0.7 g, 82%) as a white
solid. Rf 0.49 [DCM–ethyl acetate (19:1)]; Mp 158–
160 ꢁC; (Found: C, 79.43%; H, 6.62%; N, 8.91%.
C21H20N2O requires: C, 79.72%; H, 6.37%; N, 8.86%);
dH (400 MHz, CDCl3): 1.65 (9H, s, C(CH3)3), 4.73
(2H, s, quinoline–CH2–N), 7.55 (3H, m, 3Ar–H), 7.68
(1H, t, Ar–Hb or Ar–Hc), 7.79 (1H, t, Ar–Hb or Ar–
Hc), 7.90 (2H, m, 2Ar–H), 8.25 (1H, d, Ar–Ha or Ar–
Hd, Jab or Jdc 8.6 Hz), 9.18 (1H, d, Ar–Ha or Ar–Hd,
Jab or Jdc 8.3 Hz); IR (KBr) mmax 2972, 1673 (amide),
1231, 776, 699; m/z 316 (25), 301, (100), 260 (40), 231
(30), 216 (60), 204 (25), 136 (20).
5.49. 8-Formyl-2-phenyl-quinoline-4-carboxylic acid ethyl
ester (10c)
Using the same method as for the synthesis of (11), 2-
nitropropane
(1.27 g,
1.51 · 10ꢁ2 mol),
sodium
(0.273 g, 1.19 · 10ꢁ2 mol) in ethanol (14 mL) and benz-
ylic bromide (4c) (4.0 g, 1.08 · 10ꢁ2 mol) in ethanol
(40 mL) were warmed in a N2 atmosphere for 3 h. The
crude product that crystallised was filtered, washed with
cold ethanol and dried in vacuo (P2O5) to yield the title
compound (3.0 g, 91%) as fine yellow needles. Rf 0.50
[hexane–ethyl acetate (3:1)]; Mp 116–118 ꢁC; (Found:
C, 74.51%; H, 4.94%; N, 4.54%. C19H15NO3 requires:
C, 74.74%; H, 4.95%; N, 4.59%); dH (400 MHz, CDCl3):
1.53 (3H, t, O–CH2CH3), 4.58 (2H, q, O–CH2–CH3),
7.56 (3H, m, 3Ar–H), 7.76 (1H, t, Ar–Hc), 8.29 (2H,
m, 2Ar–H), 8.38 (1H, dd, Ar–Hb or Ar–Hd, Jbc or Jdc
7.1 Hz, Jbd or Jdb 1.5 Hz), 8.52 (1H, s, Ar–Ha), 9.06
(1H, dd, Ar–Hb or Ar–Hd, Jbc or Jdc 8.6 Hz, Jbd or
Jdb 1.5 Hz), 11.66 (1H, s, CHO); dC (100 MHz, CDCl3):
14.40, 62.27, 120.31, 124.01, 127.29, 127.56, 129.10,
129.57, 130.49, 131.91, 136.44, 138.13, 148.51, 157.13,
166.00, 192.75; IR (KBr) mmax 1727 (ester), 1685 (alde-
hyde), 1595, 1556, 1236, 1064, 697; m/z 305 (M+), 277
(100), 249 (60), 204 (65).
5.47. 3-Formyl-2-phenyl-quinoline-4-carboxylic acid ethyl
ester (10a)
DMSO (17 mL) was sonicated for 30 min, benzylic bro-
mide (4a) (1.0 g, 2.7 · 10ꢁ3 mol) and sodium hydrogen
carbonate (1.87 g, 2.23 · 10ꢁ2 mol) were added and the
reaction heated at 100 ꢁC for 7 min. This was cooled
in an ice/water bath, saturated NaCl solution (100 mL)
added and the product extracted into diethyl ether
(3 · 50 mL). The organic phase was washed with satu-
rated NaCl solution (2 · 35 mL) and dried over magne-
sium sulfate prior to filtration and removal of the
solvent in vacuo. The crude product was purified by col-
umn chromatography [DCM–hexane (2:1) > DCM] and
dried in vacuo (P2O5) to yield the title compound (0.6 g,
73%) as a colourless oil. Rf 0.36 [DCM]; dH (400 MHz,
CDCl3): 1.47 (3H, t, O–CH2CH3), 4.64 (2H, q, O–
CH2–CH3), 7.55 (3H, m, 3Ar–H), 7.67 (3H, m, 2Ar–
H + Ar–Hb or Ar–Hc), 7.88 (1H, t, Ar–Hb or Ar–Hc),
7.93 (1H, d, Ar–Ha or Ar–Hb, Jab or Jdc 8.6 Hz), 8.22
(1H, d, Ar–Ha or Ar–Hb, Jab or Jdc 8.5 Hz), 10.10
(1H, s, CHO); IR (KBr) mmax 1726 (ester), 1693, 1584,
1246, 1167; m/z 305 (M+, 15), 276 (30), 260 (15), 231
(30), 204 (100), 75 (30).
5.50. 3-Ethoxy-4-phenyl-3H-furo[3,4-c]quinolin-1-one
(11)
2-Nitropropane (2.54 g, 3.02 · 10ꢁ2 mol) was added to
sodium (0.546 g, 2.38 · 10ꢁ2 mol) in ethanol (25 mL)
to form a white gelatinous precipitate. This was added
to benzylic bromide (4a) (8.0 g, 2.16 · 10ꢁ2 mol) in etha-
nol (60 mL) and the reaction was warmed in a N2 atmo-
sphere for 3 h, cooled to room temperature and the
solvent removed in vacuo. The resulting solid was taken
up in DCM (100 mL), washed with water (30 mL) and
saturated NaCl solution (30 mL) and dried over magne-
sium sulfate prior to filtration and removal of the solvent
in vacuo. The crude product was purified by column
chromatography [DCM] and dried in vacuo (P2O5) to
yield the title compound (4.9 g, 74%) as a yellow crystal-
line solid. Rf 0.48 [hexane–ethyl acetate (3:1)]; Mp 129–
131 ꢁC; (Found: C, 74.52%; H, 4.87%; N, 4.48%.
5.48. 6-Formyl-2-phenyl-quinoline-4-carboxylic acid ethyl
ester (10b)
Using the same method as for the synthesis of (11),
2-nitropropane (2.54 g, 3.02 · 10ꢁ2 mol), sodium

1960
A. N. Boa et al. / Bioorg. Med. Chem. 13 (2005) 1945–1967
C19H15NO3 requires: C, 74.74%; H, 4.95%; N, 4.59%);
dH (400 MHz, CDCl3): 1.17 (3H, t, O–CH2CH3), 3.80
(1H, double quartet, O–CHH–CH3), 3.98 (1H, double
quartet, O–CHH–CH3), 6.70 (1H, s, O–CH–O), 7.54
(3H, m, 3Ar–H), 7.77 (1H, t, Ar–Hb or Ar–Hc), 7.90
(1H, t, Ar–Hb or Ar–Hc), 7.98 (2H, m, 2Ar–H), 8.31
(1H, d, Ar–Ha or Ar–Hd, Jab or Jdc 8.6 Hz), 8.93 (1H,
d, Ar–Ha or Ar–Hd, Jab or Jdc 8.3 Hz); dC (100 MHz,
CDCl3): 14.85, 66.67, 102.17, 121.66, 123.63, 128.74,
128.88, 129.26, 129.84, 130.02, 131.27, 131.45, 137.33,
137.69, 149.56, 154.50, 167.93; IR (KBr) mmax 1780 (lac-
tone), 1339 (ether), 1106, 943, 773; m/z 305 (M+, 95),
276 (30), 261 (100), 232 (45), 204 (85).
129.27, 129.95, 130.85, 138.11, 143.75, 148.68, 153.94,
169.44; IR (KBr) mmax 1772 (lactone), 1124, 782, 726;
m/z 275 (M+, 90), 246 (75), 230 (60), 218 (100), 204 (75).
5.53. 3-Morpholin-4-yl-4-phenyl-3H-furo[3,4-c]quinolin-
1-one (14)
Lactol (12) (0.1 g, 3.6 · 10ꢁ4 mol) was heated under re-
flux in morpholine (5 mL) for 4 h. The reaction was
cooled and the solvent removed in vacuo. The crude
product was purified by column chromatography
[DCM–ethyl acetate (19:1)] and dried in vacuo (P2O5)
to yield the title compound (0.12 g, 100%) as a colourless
oil. Rf 0.41 [DCM–ethyl acetate (19:1)]; dH (400 MHz,
CDCl3): 2.67 (2H, m, 2 · N–CHH–CH2–O), 3.23 (2H,
m, 2 · N–CH2–CHH–O), 3.29 (2H, m, 2 · N–CH2–
CHH–O), 6.62 (1H, s, O–CH–N), 7.54 (3H, m, 3Ar–
H), 7.76 (1H, t, Ar–Hb or Ar–Hc), 7.82 (2H, m, 2Ar–
H), 7.88 (1H, t, Ar–Hb or Ar–Hc), 8.29 (1H, d, Ar–
Ha or Ar–Hb, Jab or Jdc 8.6 Hz), 8.97 (1H, d, Ar–Ha
or Ar–Hb, Jab or Jdc 8.6 Hz); m/z 346 (M+, 50), 259
(40), 218 (100), 204 (35).
5.51. 3-Hydroxy-4-phenyl-3H-furo[3,4-c]quinolin-1-one (12)
Concentrated hydrochloric acid (10 mL) was added to
lactone (11) (2.0 g, 6.55 · 10ꢁ3 mol) and heated under
reflux for 15 min. The reaction was cooled to room tem-
perature and water (100 mL) added. The crude product
was filtered, washed with diethyl ether and dried in
vacuo (P2O5) to yield the title compound (1.8 g, 100%)
as a pale yellow solid. Rf 0.22 [hexane–ethyl acetate
(3:1)]; Mp 270–273 ꢁC; (Found: C, 73.35%; H, 4.14%;
N, 5.03%. C17H11NO3 requires: C, 73.64%; H, 4.00%;
N, 5.05%); dH (400 MHz, DMSO): 7.32 (1H, s, O–
CH–O), 7.56 (3H, m, 3Ar–H), 7.87 (1H, t, Ar–Hb or
Ar–Hc), 7.98 (1H, t, Ar–Hb or Ar–Hc), 8.10 (2H, m,
2Ar–H), 8.19 (1H, s (broad), OH), 8.28 (1H, d, Ar–Ha
or Ar–Hb, Jab or Jdc 8.0 Hz), 8.79 (1H, d, Ar–Ha or
Ar–Hb, Jab or Jdc 8.3 Hz); dC (100 MHz, DMSO):
98.40, 121.11, 122.86, 128.69, 129.09, 129.53, 129.74,
129.92, 130.48, 131.50, 137.36, 140.06, 148.50, 154.00,
167.99; IR (KBr) max 3209, 2497, 1783 (lactone),
1647, 1121; m/z 277 (M+, 35), 249 (10), 220 (10), 204
(100), 102 (40).
5.54. 3-Ethoxy-1-oxo-4-phenyl-1,3-dihydro-furo[3,4-c]-
quinoline-8-carbaldehyde (15)
Using the same method as for the synthesis of lactone
(11), 2-nitropropane (0.25 g, 3.02 · 10ꢁ3 mol), sodium
(0.57 g, 2.37 · 10ꢁ3 mol) in ethanol (6 mL) and benzylic
bromide (4d) (0.5 g, 1.08 · 10ꢁ3 mol) in ethanol (15 mL)
were warmed in a N2 atmosphere for 3 h. The crude
product was purified by column chromatography
[DCM–hexane (9:1)] and dried in vacuo (P2O5) to yield
the title compound (0.23 g, 65%) as a pale yellow solid.
Rf 0.23 [DCM–hexane (9:1)]; Mp 190–192 ꢁC; (Found:
C, 71.92%; H, 4.56%; N, 4.07%. C20H15NO4 requires:
C, 72.06%; H, 4.54%; N, 4.20%); dH (400 MHz, CDCl3):
1.20 (3H, t, O–CH2 CH3), 3.87 (1H, double quartet, O–
CHH–CH3), 4.03 (1H, double quartet, O–CHH–CH3),
6.76 (1H, s, O–CH–O), 7.59 (3H, m, 3Ar–H), 8.03
(2H, m, 2Ar–H), 8.39 (2H, m, 2Ar–H), 9.41 (1H, d,
Ar–Ha), 10.30 (1H, s, CHO); dC (100 MHz, CDCl3):
14.78, 67.01, 77.31, 102.29, 121.21, 128.05, 128.82,
128.97, 129.61, 130.49, 131.12, 132.53, 136.00, 137.04,
138.21, 151.85, 157.11, 167.36, 191.27; IR (KBr) mmax
1780 (lactone), 1700 (aldehyde), 1333 (ether); m/z 333
(M+, 85), 304 (30), 289 (100), 260 (35), 230 (60), 204
(50).
5.52. 3-Methyl-4-phenyl-3H-furo[3,4-c]quinolin-1-one
(13)
Methyl iodide (2.05 g, 1.44 · 10ꢁ2 mol) in diethyl ether
(7.5 mL) was added to magnesium (0.35 g,
1.44 · 10ꢁ2 mol) in diethyl ether (2.5 mL). This Grig-
nard reagent was added drop wise to lactol (12) (0.5 g,
1.8 · 10ꢁ3 mol) in THF (10 mL) at ꢁ78 ꢁC. The reaction
was allowed to warm to room temperature and stirred
for 18 h. Hydrochloric acid (2 M) was added and the
product extracted into ethyl acetate (2 · 30 mL). This
was washed with sodium metabisulfite (30 mL) and
dried over magnesium sulfate prior to filtration and re-
moval of the solvent in vacuo. The crude product was
purified by column chromatography [DCM–hexane
(4:1)] and dried in vacuo (P2O5) to yield the title com-
pound (0.37 g, 75%) as a pale yellow solid. Rf 0.58
[DCM]; Mp 121–123 ꢁC; (Found: C, 78.34%; H,
4.81%; N, 4.82%. C18H13NO2 requires: C, 78.53%; H,
4.76%; N, 5.09%); dH (400 MHz, CDCl3): 1.36 (3H, d,
CH–CH3) 6.13 (1H, q, CH–CH3), 7.56 (3H, m, 3Ar–
H), 7.77 (1H, t, Ar–Hb or Ar–Hc), 7.82 (2H, m, 2Ar–
H), 7.88 (1H, t, Ar–Hb or Ar–Hc), 8.31 (1H, d, Ar–
Ha or Ar–Hb, Jab or Jdc 8.6 Hz), 8.96 (1H, d, Ar–Ha
or Ar–Hb, Jab or Jdc 8.3 Hz); dC (100 MHz, CDCl3):
18.64, 77.79, 122.13, 123.31, 128.39, 129.17, 129.21,
5.55. 3,6-Dimethyl-2-phenyl-quinoline-4-carboxylic acid
dibenzylamide (16a)
Thionyl chloride (30 mL) was added drop wise to car-
boxylic acid (2d) (3.57 g, 1.28 · 10ꢁ2 mol) and the reac-
tion heated under reflux in a N2 atmosphere for 3 h. The
reaction was cooled to room temperature and the thio-
nyl chloride removed in vacuo. The last traces of thionyl
chloride were removed with diethyl ether (2 · 50 mL) to
leave the acid chloride as a yellow solid, which was dis-
solved in DCM (50 mL). This was added drop wise to
dibenzylamine (5.05 g, 2.56 · 10ꢁ2 mol) in DCM
(50 mL). The reaction was stirred at room temperature
for 3 h. Saturated sodium hydrogen carbonate (30 mL)

A. N. Boa et al. / Bioorg. Med. Chem. 13 (2005) 1945–1967
1961
was added. The organic layer was dried over magnesium
5.58. 3-Methyl-2-phenyl-quinoline-4-carboxylic acid
diisopropylamide (precursor to 17a)
sulfate prior to filtration and removal of the solvent in
vacuo. The crude product was recrystallised from etha-
nol, washed with cold ethanol and dried in vacuo
(P2O5) yield the title compound (4.8 g, 82%) as a white
solid. Rf 0.32 [DCM–ethyl acetate (19:1)]; Mp 230–
232 ꢁC; dH (400 MHz; CD2Cl2): 2.30 (3H, s, CH3),
2.45 (3H, s, CH3), 4.15 (1H, d, N–CHH–Ph, J 15.6 Hz
(gem)), 4.22 (1H, d, N–CHH–Ph, J 15.6 Hz (gem)),
4.82 (1H, d, N–CHH–Ph, J 14.2 Hz (gem)), 4.97 (1H,
d, N–CHH–Ph, J 14.2 Hz (gem)), 7.00 (2H, m, 2Ar–
H), 7.27 (3H, m, 3Ar–H), 7.62 (12H, m, 12Ar–H), 8.00
(1H, d, Ar–H); IR (KBr) mmax 1622 (amide), 1455,
1233, 700; m/z (EI, relative intensity) 456 (M+, 15),
441 (18), 365 (20), 231 (45), 217 (65).
Thionyl chloride (140 mL) was added drop wise to car-
boxylic acid (2a) (15.0 g, 2.7 · 10ꢁ2 mol) and the reac-
tion heated under reflux in a N2 atmosphere for 3 h.
The reaction was cooled to room temperature and the
thionyl chloride removed in vacuo. The last traces of
thionyl chloride were removed with diethyl ether
(250 mL) to leave the acid chloride as a yellow solid,
which was dissolved in DCM (150 mL). This was added
drop wise to diisopropylamine (11.5 g, 0.114 mol) in
DCM (150 mL). The reaction was stirred at room tem-
perature for 3 h. Saturated sodium hydrogen carbonate
(100 mL) was added. The organic layer was dried over
magnesium sulfate prior to filtration and removal of
the solvent in vacuo. Purification of the crude product
by column chromatography [DCM > DCM–ethyl ace-
tate (6:1)] and drying in vacuo (P2O5) gave the title com-
pound (14 g, 71%) as a white solid. Rf 0.37 [DCM–ethyl
acetate (19:1)]; Mp 130–132 ꢁC; (Found: C, 79.72%; H,
7.65%; N, 8.02%. C23H26N2O requires: C, 79.73%; H,
7.56%; N, 8.08%); dH (400 MHz; CDCl3): 1.06 (3H, d,
CH–CH3, J 6.6 Hz), 1.15 (3H, d, CH–CH3, J 6.8 Hz),
1.68 (3H, d, CH–CH3, J 6.8 Hz), 1.78 (3H, d, CH–
CH3, J 6.8 Hz), 2.39 (3H, s, CH3), 3.58 (1H, m, N–
CH–(CH3)2), 3.65 (1H, m, N–CH–(CH3)2), 7.50 (6H,
m, 5Ar–H + Ar–Hb or Ar–Hc), 7.68 (1H, t, Ar–Hb or
Ar–Hc), 7.75 (1H, d, Ar–Ha or Ar–Hd, Jab or Jdc
8.3 Hz), 8.12 (1H, d, Ar–Ha or Ar–Hd, Jab or Jdc
8.3 Hz); dC (100 MHz, CDCl3): 17.33, 20.34, 20.61,
20.89, 20.97, 46.29, 51.22, 123.54, 123.79, 124.16,
126.91, 128.25, 128.76, 129.09, 129.63, 140.56, 143.37,
146.32, 160.84, 167.57; IR (KBr) mmax 2976, 1636
(amide), 1447, 1316; m/z 346 (M+, 20), 331 (15), 303
(20), 260 (10), 246 (70), 217 (100).
5.56. 3,6-Dimethyl-2-phenyl-quinoline-4-carboxylic acid
diethylamide (16b)
Using the same method as for the synthesis of amide
(16b), carboxylic acid (2d) (2.25 g, 8.0 · 10ꢁ3 mol) was
refluxed in thionyl chloride (30 mL) for 3 h. The acid
chloride in DCM (30 mL) was added to diethylamine
(1.17 g, 1.6 · 10ꢁ2 mol) in DCM (30 mL) and stirred at
room temperature for 3 h. Purification of the crude prod-
uct by column chromatography [DCM–ethyl acetate
(19:1) > (1:1)] and drying in vacuo (P2O5) gave the title
compound (2.2 g, 87%) as a white solid. Rf 0.16 [hex-
ane–ethyl acetate (3:1)]; Mp 205–207 ꢁC; dH (400 MHz;
CDCl3): 0.99 (3H, t, N–CH2–CH3), 1.39 (3H, t, N–
CH2–CH3), 2.36 (3H, s, CH3), 2.51 (3H, s, CH3), 3.13
(2H, q, N–CH2–CH3), 3.40 (1H, m, N–CHH–CH3),
3.84 (1H, m, N–CHH–CH3), 7.48 (7H, m, 7Ar–H),
8.02 (1H, d, Ar–H); IR (KBr) mmax 3445, 1636 (amide),
1474, 1438; m/z (EI, relative intensity) 332 (M+, 30),
317 (35), 260 (60), 230 (95), 217 (100), 128 (35).
5.57. 3,6-Dimethyl-2-phenyl-quinoline-4-carboxylic acid
diisopropylamide (16c)
5.59. 3-Bromomethyl-2-phenyl-quinoline-4-carboxylic
acid diisopropylamide (17a)
Usingthe same method as for the synthesis of amide (16a),
carboxylic acid (2d) (2.25 g, 8.0 · 10ꢁ3 mol) was refluxed
in thionyl chloride (30 mL) for 3 h. The acid chloride in
DCM (30 mL) was added to diisopropylamine (1.62 g,
1.6 · 10ꢁ2 mol) in DCM (30 mL) and heated under reflux
for 3 h. Purification of the crude product by column chro-
matography [DCM–ethyl acetate (19:1) > (1:1)] and dry-
ing in vacuo (P2O5) gave the title compound (2.0 g, 70%)
as a white solid. Rf 0.17 [DCM–ethyl acetate (19:1)]; Mp
209–211 ꢁC; dH (400 MHz; CDCl3): (Found: C, 79.81%;
H, 7.64%; N, 7.67%. C24H28N2O requires: C, 79.96%;
H, 7.83%; N, 7.77%); 1.06 (3H, d, CH–CH3, J 6.6 Hz),
1.14 (3H, d, CH–CH3, J 6.6 Hz), 1.68 (3H, d, CH–CH3,
J 6.8 Hz), 1.79 (3H, d, CH–CH3, J 6.6 Hz), 2.37 (3H, s,
CH3), 2.52 (3H, s, CH3), 3.58 (1H, m, N–CH–(CH3)2),
3.65 (1H, m, N–CH–(CH3)2), 7.50 (7H, m, 7Ar–H), 8.01
(1H, d, Ar–H); dC (100 MHz, CDCl3): 17.37, 20,43,
20.70, 20.95, 21.00, 21.84, 46.32, 51.20, 123.11, 123.57,
123.72, 128.13, 128.27, 128.86, 129.38, 131.37, 136.78,
140.75, 142.75, 145.01, 159.94, 167.86; IR (KBr) mmax
2980, 1633 (amide), 1450, 1318; m/z (EI, relative intensity)
360 (M+, 40), 345 (25), 317 (20), 260 (90), 231 (100), 216
(80).
Using the same method as for the synthesis of benzylic
bromide (4a), the requisite amide (see above) (5.0 g,
1.44 · 10ꢁ2 mol) was heated in carbon tetrachloride
(150 mL) with NBS (2.83 g, 1.59 · 10ꢁ2 mol) and benzoyl
peroxide (0.34 g, 1.44 · 10ꢁ3 mol) for 3 h. The crude
product was purified by column chromatography
[DCM > DCM–ethyl acetate (19:1)] and dried in vacuo
(P2O5) to yield the title compound (4.75 g, 78%) as a white
solid. Rf 0.44 [DCM–ethyl acetate (19:1)]; Mp 141–
144 ꢁC; (Found: C, 64.98%; H, 6.10%; N, 6.57%.
C23H25N2OBr requires: C, 64.94%; H, 5.92%; N,
6.59%); dH (400 MHz; CDCl3): 1.07 (3H, d, CH–CH3, J
6.6 Hz), 1.28 (3H, d, CH–CH3, J 6.6 Hz), 1.70 (3H, d,
CH–CH3, J 6.8 Hz), 1.79 (3H, d, CH–CH3, J 6.8 Hz),
3.56 (1H, m, N–CH–(CH3)2), 3.69 (1H, m, N–CH–
(CH3)2), 4.57 (1H, d, CHHBr, J 10.7 Hz gem), 4.72 (1H,
d, CHHBr, J 10.7 Hz gem), 7.51 (3H, m, 3Ar–H), 7.58
(1H, t, Ar–Hb or Ar–Hc), 7.68 (2H, m, 2Ar–H), 7.75
(1H, m, Ar–Hb or Ar–Hc), 7.83 (1H, d, Ar–Ha or Ar–
Hd, Jab or Jdc 8.6 Hz), 8.17 (1H, d, Ar–Ha or Ar–Hd,
Jab or Jdc 8.0 Hz); dC (100 MHz, CDCl3): 20.53, 20.60,
21.00, 21.24, 27.87, 46.81, 51.14, 123.40, 124.47, 125.31,
127.35, 128.50, 128.76, 128.82, 129.99, 130.75, 139.69,

1962
A. N. Boa et al. / Bioorg. Med. Chem. 13 (2005) 1945–1967
144.92, 147.34, 161.14, 166.19; IR (KBr) mmax 2982, 1629
(amide), 1442, 771; m/z 427 (M+, 20), 425 (M+, 20), 345
(50), 301 (35), 244 (35), 217 (100).
bromide (17a) (8.5 g, 2.0 · 10ꢁ2 mol) in ethanol (36 mL)
were warmed in a N2 atmosphere for 3 h. The crude
product was washed with cold ethanol and dried in
vacuo (P2O5) to yield the title compound (6.7 g, 93%)
as a white solid. Rf 0.42 [DCM–ethyl acetate (19:1)];
Mp 138–140 ꢁC; dH (400 MHz; CDCl3): 1.04 (3H, d,
CH–CH3, J 6.6 Hz), 1.19 (3H, d, CH–CH3, J 6.6 Hz),
1.79 (6H, m, 2CH–CH3), 3.46 (1H, m, N–CH–(CH3)2),
3.69 (1H, m, N–CH–(CH3)2), 7.54 (3H, m, 3Ar–H),
7.65 (3H, m, 2Ar–H + Ar–Hb or Ar–Hc), 7.87 (1H, t,
Ar–Hb or Ar–Hc), 8.01 (1H, d, Ar–Ha or Ar–Hd, Jab
or Jdc 8.3 Hz), 8.20 (1H, d, Ar–Ha or Ar–Hd, Jab or
Jdc 8.5 Hz), 10.10 (1H, s, CHO); dC (100 MHz, CDCl3):
19.79, 20.10, 20.93, 20.97, 46.62, 51.69, 122.62, 123.39,
126.45, 127.90, 128.76, 129.51, 130.09, 130.28, 132.58,
138.34, 146.44, 149.53, 160.63, 166.25, 191.05; IR
(KBr) mmax 2980, 1639 (amide), 1551, 1447, 1353; m/z
360 (M+, 10), 317 (85), 275 (80), 260 (60), 232 (50),
204 (80), 100 (100).
5.60. 6-Methyl-2-phenyl-quinoline-4-carboxylic acid
diisopropylamide (precursor to 17b)
Using the same method as for the synthesis of amide
above, carboxylic acid (2b) (16.0 g, 6.1 · 10ꢁ2 mol) was
heated at reflux in thionyl chloride (160 mL) for 3 h.
The acid chloride in DCM (150 mL) was added to diiso-
propylamine (12.34 g, 0.12 mol) in DCM (150 mL) and
heated under reflux for 3 h. Purification of the crude
product by column chromatography [DCM > DCM–
ethyl acetate (3:1)] and drying in vacuo (P2O5) gave
the title compound (16 g, 76%) as a white solid. Rf 0.6
[DCM–ethyl acetate (19:1)]; Mp 180–182 ꢁC; (Found:
C, 79.46%; H, 7.31%; N, 8.15%. C23H26N2O requires:
C, 79.73%; H, 7.56%; N, 8.08%); dH (400 MHz; CDCl3):
1.08 (3H, d, CH–CH3, J 6.6 Hz), 1.11 (3H, d, CH–CH3,
J 6.8 Hz), 1.68 (3H, d, CH–CH3, J 6.8 Hz), 1.74 (3H, d,
CH–CH3, J 6.8 Hz), 2.53 (3H, s, CH3), 3.63 (2H, m,
2 · N–CH–(CH3)2), 7.51 (5H, m, 5Ar–H), 7.66 (1H, s,
Ar–Ha), 8.08 (1H, d, Ar–H, J 9.0 Hz), 8.14 (2H, m,
2Ar–H); dC (100 MHz, CDCl3): 20.75, 20.78, 20.80,
20.85, 33.26, 46.48, 51.38, 114.96, 123.17, 124.70,
127.63, 127.68, 128.99, 129.03, 129.84, 130.94, 131.13,
136.46, 139.08, 145.20, 148.25, 157.77, 167.57; IR
(KBr) mmax 2964, 1635 (amide), 1438, 1357, 702; m/z
346 (M+, 30), 246 (100), 218 (55), 203 (15).
5.63. 6-Formyl-2-phenyl-quinoline-4-carboxylic acid
diisopropylamide (18b)
Using the same method as for the synthesis of lactone
(11), 2-nitropropane (1.61 g, 1.8 · 10ꢁ2 mol), sodium
(0.327 g, 1.4 · 10ꢁ2 mol) in ethanol (14 mL) and benz-
ylic bromide (17b) (5.5 g, 1.3 · 10ꢁ2 mol) in ethanol
(20 mL) were warmed in a N2 atmosphere for 3 h. The
crude product was purified by column chromatography
[DCM–ethyl acetate (5:1)] and dried in vacuo (P2O5) to
yield the title compound (4.0 g, 85%) as a white solid. Rf
0.27 [hexane–ethyl acetate (3:1)]; Mp 176–178 ꢁC;
(Found: C, 76.36%; H, 6.78%; N, 7.77%. C23H24N2O2
requires: C, 76.64%; H, 6.71%; N, 7.77%); dH
(400 MHz; CDCl3): 1.09 (3H, d, CH–CH3, J 6.6 Hz),
1.16 (3H, d, CH–CH3, J 6.6 Hz), 1.69 (3H, d, CH–
CH3, J 6.6 Hz), 1.77 (3H, d, CH–CH3, J 6.6 Hz), 3.61
(1H, m, N–CH–(CH3)2), 3.69 (1H, m, N–CH–(CH3)2),
7.54 (3H, m, 3Ar–H), 7.80 (1H, s, Ar–Ha), 8.20 (3H,
m, 2Ar–H + Ar–Hc), 8.29 (1H, d, Ar–Hd, Jdc 8.5 Hz),
8.32 (1H, d, Ar–Hb, Jbc 2.0 Hz), 10.15 (1H, s, CHO);
dC (100 MHz, CDCl3): 20.75, 20.84, 20.87, 46.67,
51.46, 115.37, 123.03, 127.51, 127.81, 129.08, 130.38,
130.42, 131.49, 134.46, 138.57, 146.50, 151.30, 159.83,
167.00, 191.10; IR (KBr) mmax 1690, 1630 (amide),
1450, 1355, 1313; m/z 360 (M+, 25), 317 (20), 260
(100), 232 (35), 204 (30).
5.61. 6-Bromomethyl-2-phenyl-quinoline-4-carboxylic
acid diisopropylamide (17b)
Using the same method as for the synthesis of benzylic
bromide (4a), the requisite amide (see above) (10.16 g,
2.9 · 10ꢁ2 mol) was heated in carbon tetrachloride
(150 mL) with NBS (5.74 g, 3.2 · 10ꢁ2 mol) and benzoyl
peroxide (0.7 g, 2.9910ꢁ3 mol) for 3 h. The crude prod-
uct was purified by column chromatography
[DCM > DCM–ethyl acetate (4:1)] and dried in vacuo
(P2O5) to yield the title compound (10.7 g, 87%) as a
white solid. Rf 0.34 [hexane–ethyl acetate (3:1)]; Mp
188–190 ꢁC; (Found: C, 65.14%; H, 5.97%; N, 6.34%.
C23H25N2OBr requires: C, 64.94%; H, 5.92%; N,
6.59%); dH (400 MHz; CDCl3): 1.11 (6H, t, 2 · CH–
CH3), 1.69 (3H, d, CH–CH3, J 6.8 Hz), 1.76 (3H, d,
CH–CH3, J 6.8 Hz), 3.60 (1H, m, N–CH–(CH3)2), 3.68
(1H, m, N–CH–(CH3)2), 4.61 (1H, d, CHHBr, J
10.5 Hz gem), 4.69 (1H, d, CHHBr, J 10.5 Hz gem),
7.52 (3H, m, 3Ar–H), 7.71 (1H, s, Ar–Ha), 7.75 (1H,
dd, Ar–Hc, Jcb 2.0 Hz, Jcd 8.8 Hz), 7.81 (1H, d, Ar–
Hb, Jbc 2.0 Hz), 8.15 (3H, m, 2Ar–H + Ar–Hd); IR
(KBr) mmax 1629 (amide), 1444, 1355, 1315; m/z 426
(M+, 25), 424 (M+, 25), 383 (5), 381 (55), 345 (90),
326 (55), 324 (55), 246 (100), 217 (60).
5.64. 3-Oxiranyl-2-phenyl-quinoline-4-carboxylic acid
diisopropylamide (19a)
Potassium tert-butoxide (4.1 g, 3.65 · 10ꢁ2 mol) and
trimethylsulfonium iodide (8.15 g, 4.0 · 10ꢁ2 mol) were
stirred in tert-butanol (200 mL) under a N2 atmosphere
at 30 ꢁC for 20 min. Arylaldehyde (18a) (6.0 g,
1.66 · 10ꢁ2 mol) was added and the reaction stirred for
a further 30 min. Diethyl ether (100 mL) and water
(200 mL) were then added, the diethyl ether layer col-
lected, washed with saturated NaCl solution (100 mL)
and dried over magnesium sulfate prior to filtration
and removal of the solvent in vacuo. The product was
filtered, washed with cold diethyl ether and dried in
vacuo (P2O5) to yield the title compound (4.8 g, 78%)
5.62. 3-Formyl-2-phenyl-quinoline-4-carboxylic acid
diisopropylamide (18a)
Using the same method as for the synthesis of lactone
(11), 2-nitropropane (2.35 g, 2.8 · 10ꢁ2 mol), sodium
(0.50 g, 2.2 · 10ꢁ2 mol) in ethanol (25 mL) and benzylic

A. N. Boa et al. / Bioorg. Med. Chem. 13 (2005) 1945–1967
1963
as a 5:1 mixture of atropisomers. White solid. Rf 0.21
[DCM–ethyl acetate (19:1)]; Mp 150–152 ꢁC; (Found:
C, 77.29%; H, 7.27%; N, 7.78%. C24H26N2O2 requires:
C, 76.98%; H, 7.00%; N, 7.48); dH (400 MHz; CDCl3,
major atropisomer): 0.99 (3H, d, CH–CH3, J 6.6 Hz),
1.21 (3H, d, CH–CH3, J 6.6 Hz), 1.68 (3H, d, CH–
CH3, J 6.8 Hz), 1.74 (3H, d, CH–CH3, J 7.1 Hz), 3.00
(1H, dd, CHOCHH, J 4.2 Hz, J 6.4 Hz), 3.29 (1H, dd,
CHOCHH, J 2.7 Hz, J 6.4 Hz), 3.48 (1H, m, N–CH–
(CH3)2), 3.62 (1H, m, N–CH–(CH3)2), 3.89 (1H, dd,
CHOCH2, J 2.7 Hz, J 4.2 Hz), 7.49 (3H, m, 3Ar–H),
7.55 (1H, t, Ar–Hb or Ar–Hc), 7.70 (3H, m, 2Ar–
H + Ar–Hb or Ar–Hc), 7.87 (1H, d, Ar–Ha or Ar–Hd,
Jab or Jdc 8.6 Hz), 8.14 (1H, d, Ar–Ha or Ar–Hd, Jab
or Jdc 7.5 Hz); dC (100 MHz, CDCl3): 19.42, 19.56,
20.79, 20.84, 46.28, 51.00, 51.42, 51.61, 123.49, 124.06,
124.70, 127.21, 128.52, 128.90, 129.19, 129.80, 130.00,
140.01, 141.45, 147.17, 159.39, 166.64; m/z 374 (M+,
5), 359 (10), 331 (50), 274 (100), 259 (65), 246 (55), 230
(25), 217 (85).
chromatography [ethyl acetate > ethyl acetate–methanol
(9:1)] and dried in vacuo (P2O5). (21a); white solid (0.2 g,
83%); Rf 0.25 [ethyl acetate–methanol (2:1)]; Mp 149–
152 ꢁC; (Found: C, 74.87%; H, 8.21%; N, 9.45%.
C28H37N3O2 requires: C, 75.13%; H, 8.33%; N,
9.39%); dH (400 MHz; CDCl3, mixture of rotamers
(1:1)): 1.10 (12H, m, 2 · CH–CH3 + 2 · N–CH2–CH3),
1.69 (3H, dd, CH–CH3), 1.75 (3H, dd, CH–CH3), 2.51
(1H, t, CH(OH)–CHH), 2.62 (2H, m, N–CH2–CH3),
2.75 (3H, m, N–CH2–CH3 + CH(OH)–CHH), 3.62
(2H, m, 2 · N–CH–(CH3)2), 4.81 (1H, t, CH(OH)–
CH2), 7.50 (3H, m, 3Ar–H), 7.67 (0.5H, dd, Ar–Hc,
Jcb 1.7 Hz, Jcd 8.7 Hz), 7.69 (0.5H, s, Ar–Ha), 7.71
(0.5H, s, Ar–Ha), 7.78 (0.5H, d, Ar–Hb, 1.7 Hz), 7.82
(0.5H, dd, Ar–Hc, Jcb 1.7 Hz, Jcd 8.7 Hz), 7.94 (0.5H,
d, Ar–Hb, 1.7 Hz), 8.15 (3H, m, 2Ar–H + Ar–Hd); m/z
447 (M+), 416, 361, 317, 260, 86 (100); (20b); pale yellow
oil (0.017 g, 7%); Rf 0.32 [ethyl acetate–methanol (9:1)];
dH (400 MHz; CDCl3, mixture of rotamers (1:1)): 1.07
(3H, d, CH–CH3, J 6.8 Hz), 1.13 (9H, m, CH–
CH3 + 2 · N–CH2–CH3), 1.69 (3H, d, CH–CH3, J
6.7 Hz), 1.72 (3H, dd, CH–CH3), 2.35 (2H, m, N–
CH2–CH3), 2.80 (2H, m, N–CH2–CH3), 3.64 (2H, m,
2 · N–CH–(CH3)2), 3.76 (1H, m), 4.02 (1H, m), 4.15
(1H, m), 7.51 (3H, m, 3Ar–H), 7.63 (2H, m, 2Ar–H),
7.70 (1H, d, Ar–H), 8.15 (3H, m, 3Ar–H); m/z 447
(M+), 430, 416 (100), 374 (5), 358 (5), 259 (5).
5.65. 6-Oxiranyl-2-phenyl-quinoline-4-carboxylic acid
diisopropylamide (19b)
Using the same method as for the synthesis of epoxide
(19a), arylaldehyde (18b) (1.0 g, 2.77 · 10ꢁ3 mol), potas-
sium tert-butoxide (0.68 g, 6.09 · 10ꢁ3 mol) and trim-
ethylsulfonium iodide (1.36 g, 6.65 · 10ꢁ3 mol) were
stirred in tert-butanol (50 mL) at 30 ꢁC for 30 min.
The crude product was purified by column chromatog-
raphy [DCM > DCM–ethyl acetate (4:1)] and dried in
vacuo (P2O5) to yield the title compound (0.7 g, 67%)
as a 1:1 mixture of rotamers. White solid; Rf 0.43
[DCM–ethyl acetate (19:1)]; Mp 195–197 ꢁC; dH
(400 MHz; CDCl3, mixture of rotamers (1:1)): 1.11
(6H, m, 2 · CH–CH3), 1.16 (3H, d, CH–CH3, J
6.6 Hz), 1.69 (3H, d, CH–CH3, J 6.6 Hz), 1.75 (3H,
dd, CH–CH3), 2.85 (0.5H, dd, CHOCHH, J 2.5 Hz, J
5.4 Hz), 2.88 (0.5H, dd, CHOCHH, J 2.5 Hz, J
5.4 Hz), 3.22 (1H, m, CHOCHH), 3.62 (2H, m, 2 · N–
CH–(CH3)2), 4.01 (1H, m, CHOCH2), 7.51 (3.5H, m,
3Ar–H + 0.5Ar–Hc), 7.64 (0.5H, dd, Ar–Hc, Jcb
2.0 Hz, Jcd 8.7 Hz), 7.69 (0.5H, s, Ar–Ha), 7.70 (0.5H,
s, Ar–Ha), 7.71 (0.5H, d, Ar–Hb, Jbc 2.0 Hz), 7.81
(0.5H, d, Ar–Hb–Hb, Jbc 2.0 Hz), 8.15 (3H, m, 2Ar–
H + Ar–Hd); dC (100 MHz, CDCl3): 20.60, 20.76,
20.79, 20.83, 20.86, 20.91, 46.46, 46.49, 51.23, 51.33,
51.36, 51.59, 52.17, 52.42, 114.88, 114.92, 121.00,
122.37, 123.10, 123.22, 126.51, 127.60, 127.81, 128.97,
129.73, 130.54, 130.83, 136.53, 136.65, 139.18, 144.94,
145.08, 148.52, 148.62, 157.38, 167.69, 167.73; IR
(KBr) mmax 1633 (amide), 1443, 1350, 1315, 835, 698;
m/z 374 (M+, 40), 331 (15), 274 (100), 246 (40), 217 (30).
5.67. 6-(1-Hydroxy-2-morpholin-4-yl-ethyl)-2-phenyl-
quinoline-4-carboxylic acid diisopropylamide (20b) and
6-(2-hydroxy-1-morpholin-4-yl-ethyl)-2-phenyl-quinoline-
4-carboxylic acid diisopropylamide (21b)
Epoxide (19b) (0.2 g, 5.34 · 10ꢁ4 mol) and morphol-
ine (0.093 g, 1.07 · 10ꢁ3 mol) were heated at reflux in
ethanol (5 mL) for 2 h. The solvents were removed in
vacuo and the crude products were purified by column
chromatography [ethyl acetate > ethyl acetate–methanol
(9:1)] and dried in vacuo (P2O5). (20b); white solid (0.2 g,
83%); Rf 0.44 [ethyl acetate–methanol (9:1)]; Mp 109–
111 ꢁC; dH (400 MHz; CDCl3, mixture of rotamers
(1:1)): 1.10 (6H, m, 2 · CH–CH3), 1.68 (3H, dd, CH–
CH3), 1.75 (3H, t, CH–CH3, J 6.7 Hz), 2.54 (3H, m
(broad), 2 · N–CHH–CH2–O + CH(OH)–CHH), 2.65
(1H, m, CH(OH)–CHH), 2.80 (2H, m (broad), 2 · N–
CHH–CH2–O), 3.58 (2H, m, 2 · N–CH–(CH3)2), 3.79
(4H, m, 2 · N–CH2–CH2–O), 4.94 (1H, t, CH(OH)–
CH2), 7.52 (3H, m, 3Ar–H), 7.65 (0.5H, dd, Ar–Hc,
Jcb 1.7 Hz, Jcd 8.7 Hz), 7.69 (0.5H, s, Ar–Ha), 7.71
(0.5H, s, Ar–Ha), 7.78 (0.5H, d, Ar–Hb, Jbc 1.7 Hz),
7.81 (0.5H, dd, Ar–Hc, Jcb 1.7 Hz, Jcd 8.7 Hz), 7.96
(0.5H, d, Ar–Hb, Jbc 1.7 Hz), 8.17 (3H, m, 2Ar–
H + Ar–Hd); m/z 461 (M+), 416, 362, 260, 233, 204,
100 (100). (21b); white solid (0.02, 8%); Rf 0.63 [ethyl
acetate–methanol (9:1)]; Mp 176–178 ꢁC; (Found: C,
72.57%; H, 7.65%; N, 9.24%. C28H35N3O3 requires: C,
72.86%; H, 7.64%; N, 9.10%); dH (400 MHz; CDCl3,
mixture of rotamers (1:1)): 1.07 (3H, t, CH–CH3), 1.13
(3H, dd, CH–CH3), 1.69 (3H, d, CH–CH3, J 6.8 Hz),
1.73 (3H, d, CH–CH3, J 6.5 Hz), 2.50 (2H, m (broad),
2 · N–CHH–CH2–O), 2.60 (2H, m (broad), 2 · N–
CHH–CH2–O), 3.71 (7H, m, 2 · N–CH2–CH2–
O + 2 · N–CH–(CH3)2 + 1H), 3.83 (1H, m), 4.02 (1H,
5.66. 6-(2-Diethylamino-1-hydroxy-ethyl)-2-phenyl-quin-
oline-4-carboxylic acid diisopropylamide (20a) and 6-
(1-diethylamino-2-hydroxy-ethyl)-2-phenyl-quinoline-4-
carboxylic acid diisopropylamide (21a)
Epoxide (19b) (0.2 g, 5.34 · 10ꢁ4 mol) and diethylamine
(0.078 g, 1.07 · 10ꢁ3 mol) were heated at reflux in
ethanol (5 mL) for 2 h. The solvents were removed in
vacuo and the crude products were purified by column

1964
A. N. Boa et al. / Bioorg. Med. Chem. 13 (2005) 1945–1967
m), 7.51 (3H, m, 3Ar–H), 7.67 (3H, m, 3Ar–H), 8.17
(3H, m, 3Ar–H); dC (100 MHz, CDCl3): 20.53, 20.68,
20.75, 46.33, 50.24, 50.48, 51.19, 60.97, 61.44, 65.81,
67.16, 70.43, 70.66, 114.67, 122.90, 122.97, 124.03,
124.19, 127.54, 128.90, 129.65, 130.18, 130.94, 135.67,
136.28, 139.10, 144.93, 145.02, 148.13, 148.19, 157.36,
157.45; IR (KBr) mmax 1631 (amide), 1611, 1449, 1361,
1116; m/z 461 (M+), 430 (100), 388 (5), 372 (5), 302 (5).
0 ꢁC. This was stirred for 10 min and a further 30 min at
room temperature. Epoxide (19b) (0.4 g, 1.07 ·
10ꢁ3 mol) in THF (10 mL) was added drop wise and
stirred for 30 min at room temperature. Water (20 mL)
was added, THF removed in vacuo and the product ex-
tracted into DCM (2 · 30 mL). This was washed with
saturated NaCl solution (30 mL) and dried over magne-
sium sulfate prior to filtration and removal of the sol-
vent in vacuo. The crude product was purified by
column chromatography [ethyl acetate > ethyl acetate–
methanol (9:1)] and dried in vacuo (P2O5) to yield the ti-
tle compound (0.42 g, 86%) as a 1:1 mixture of rotamers
(spectroscopic data detailed above).
5.68. 6-(1-Hydroxy-2-pyrrolidin-1-yl-ethyl)-2-phenyl-
quinoline-4-carboxylic acid diisopropylamide (20c) and
6-(2-hydroxy-1-pyrrolodin-1-yl-ethyl)-2-phenyl-quinoline-
4-carboxylic acid diisopropylamide (21c)
Epoxide (19b) (0.2 g, 5.34 · 10ꢁ4 mol) and pyrrol-
idine (0.076 g, 1.07 · 10ꢁ3 mol) were heated at reflux in
ethanol (5 mL) for 2 h. The solvents were removed in
vacuo and the crude products were purified by column
chromatography [ethyl acetate–methanol (2:1) > metha-
nol] and dried in vacuo (P2O5). (20c); white solid (0.2 g,
83%); Rf 0.29 [ethyl acetate–methanol (2:1)]; Mp 166–
168 ꢁC; (Found: C, 75.18%; H, 7.94%; N, 9.51%.
C28H35N3O2 requires: C, 75.47%; H, 7.92%; N,
9.43%); dH (400 MHz; CDCl3, mixture of rotamers
(1:1)): 1.10 (6H, m, 2 · CH–CH3), 1.68 (3H, dd, CH–
CH3), 1.74 (3H, dd, CH–CH3), 1.83 (4H, m, 2 · N–
CH2–CH2), 2.60 (3H, m, 2 · N–CHH–CH2 +
CH(OH)–CHH), 2.82 (3H, m, 2 · N–CHH–CH2 +
CH(OH)–CHH), 3.62 (2H, m, 2 · N–CH–(CH3)2),
4.97 (1H, m, CH(OH)–CH2), 7.50 (3H, m, 3Ar–H),
7.69 (1.5H, m, Ar–Ha + Ar–Hc), 7.79 (0.5H, d, Ar–
Hb, Jbc 2.0 Hz), 7.83 (0.5H, dd, Ar–Hc, Jcb 2.0 Hz, Jcd
9.0 Hz), 7.94 (0.5H, d, Ar–Hb, Jbc 2.0 Hz), 8.16 (3H,
m, 2Ar–H + Ar–Hd); dC (100 MHz, CDCl3): 20.49,
20.60, 20.71, 20.76, 23.65, 46.30, 51.22, 51.29, 53.83,
63.49, 63.84, 70.30, 70.60, 114.60, 120.88, 121.54,
122.92, 123.05, 127.49, 128.22, 128.49, 128.85, 129.48,
129.88, 130.30, 139.11, 139.28, 141.32, 141.60, 144.99,
145.15, 147.98, 148.21, 156.95, 167.90; m/z 445 (M+),
411, 361, 260, 233, 204 (100), 84 (100). (21c); white solid
(0.025 g, 10%); Rf 0.27 [ethyl acetate–methanol (4:1)];
Mp 169–171 ꢁC; (Found: C, 75.29%; H, 8.01%; N,
9.74%. C28H35N3O2 requires: C, 75.47%; H, 7.92%; N,
9.43%); dH (400 MHz; CDCl3, mixture of rotamers
(1:1)): 1.07 (3H, dd, CH–CH3), 1.11 (3H, d, CH–CH3,
J 6.5 Hz), 1.68 (3H, d, CH–CH3, J 6.7 Hz), 1.73 (3H,
d, CH–CH3, J 6.7 Hz), 1.75 (4H, m (broad), 2 · N–
CH2–CH2), 2.57 (4H, m (broad), 2 · N–CH2–CH2),
3.63 (3H, m, 2 · N–CH–(CH3)2 + 1H), 3.91 (2H, m),
7.51 (3H, m, 3Ar–H), 7.75 (3H, m, 3Ar–H), 8.16 (3H,
m, 3Ar–H); dC (100 MHz, CDCl3): 20.58, 20.76, 20.82,
23.21, 46.35, 51.10, 51.23, 51.55, 64.03, 64.69, 69.43,
70.06, 114.65, 122.89, 122.97, 123.96, 124.04, 127.57,
128.92, 129.59, 130.16, 130.19, 130.72, 130.99, 138.27,
138.92, 139.29, 144.99, 145.10, 148.15, 148.21, 157.21,
158.28, 167.79; m/z 445 (M+), 430, 414 (100), 372 (5),
356 (5).
5.70. 6-(2-Hydroxy-1-pyrrolodin-1-yl-ethyl)-2-phenyl-
quinoline-4-carboxylic acid diisopropylamide (21c)
Using the same method as for the synthesis of b-amino
alcohol (21b), epoxide (19b) (0.2 g, 5.34 · 10ꢁ4 mol), n-
butyl lithium (0.67 mL, 1.07 · 10ꢁ3 mol) and pyrrolidine
(0.15 g, 2.14 · 10ꢁ3 mol) in THF (5 mL) were stirred for
30 min. The crude product was purified by column chro-
matography [ethyl acetate > ethyl acetate–methanol
(4:1)] and dried in vacuo (P2O5) to yield the title com-
pound (0.21 g, 89%) as a 1:1 mixture of rotamers (spec-
troscopic data detailed above).
5.71. 3-(2-Diethylamino-1-hydroxyl-ethyl)-2-phenyl-quin-
oline-4-carboxylic acid diisopropylamide (22a)
Epoxide (19a) (0.2 g, 5.34 · 10ꢁ4 mol) and diethyl-
amine (0.078 g, 1.07 · 10ꢁ3 mol) were heated at reflux
in ethanol (5 mL) for 16 h. The solvents were removed
in vacuo and the crude product was purified by column
chromatography
[DCM–ethyl
acetate
(19:1) >
(4:1) > ethyl acetate] and dried in vacuo (P2O5) to yield
the title compound (0.21 g, 86%) as a 5:1 mixture of
atropisomers. Colourless oil; Rf 0.19 [ethyl acetate–
methanol (9:1)]; dH (400 MHz; CDCl3, major atrop-
isomer): 0.89 (6H, t, 2 · N–CH2CH3), 0.99 (3H, d,
CH–CH3, J 6.6 Hz), 1.21 (3H, d, CH–CH3, J 6.5 Hz),
1.61 (3H, d, CH–CH3, J 6.8 Hz), 1.76 (3H, d, CH–
CH3,
J
6.8 Hz), 2.33 (5H, m, 2 · N–CH2–
CH3 + CH(OH)–CHH), 3.07 (1H, t, CH(OH)–CHH),
3.58 (2H, m, 2 · N–CH–(CH3)2), 4.90 (1H, d,
CH(OH)–CH2), 7.45 (5H, m, Ar–H), 7.53 (1H, t, Ar–
Hb or Ar–Hc), 7.69 (1H, t, Ar–Hb or Ar–Hc), 7.95
(1H, d, Ar–Ha or Ar–Hd, Jab or Jdc 8.5 Hz), 8.10 (1H,
d, Ar–Ha or Ar–Hd, Jab or Jdc 8.5 Hz); m/z 447 (M+),
429, 416, 375, 361, 347, 317.
5.72. 3-(1-Hydroxy-2-morpholin-1-yl-ethyl)-2-phenyl-
quinoline-4-carboxylic acid diisopropylamide (22b)
Epoxide (19a) (0.2 g, 5.34 · 10ꢁ4 mol) and morpholine
(0.093 g, 1.07 · 10ꢁ3 mol) were heated at reflux in etha-
nol (5 mL) for 4 h. The solvents were removed in vacuo
and the crude product was purified by column chroma-
tography [DCM–ethyl acetate (2:1) > ethyl acetate] and
dried in vacuo (P2O5) to yield the title compound
(0.22 g, 90%) as a 5:1 mixture of atropisomers. White so-
lid; Rf 0.59 [ethyl acetate]; Mp 176–178 ꢁC; (Found: C,
72.89%; H, 7.90%; N, 9.32%. C28H35N3O3 requires: C,
5.69. 6-(2-Hydroxy-1-morpholin-4-yl-ethyl)-2-phenyl-
quinoline-4-carboxylic acid diisopropylamide (21b)
n-Butyl lithium (1.34 mL, 2.14 · 10ꢁ3 mol) was added to
morpholine (0.37 g, 4.27 · 10ꢁ3 mol) in THF (10 mL) at

A. N. Boa et al. / Bioorg. Med. Chem. 13 (2005) 1945–1967
1965
72.86%; H, 7.64%; N, 9.10%); dH (400 MHz; CDCl3,
major atropisomer): 1.00 (3H, d, CH–CH3, J 6.7 Hz),
1.21 (3H, d, CH–CH3, J 6.7 Hz), 1.61 (3H, d, CH–
CH3, J 6.7 Hz), 1.76 (3H, d, CH–CH3, J 6.7 Hz), 2.25
(2H, s (broad), 2 · N–CHH–CH2–O), 2.35 (3H, m
(broad), 2 · N–CHH–CH2–O + CH(OH)–CHH), 3.15
(1H, t, CH(OH)–CHH), 3.54 (1H, m, N–CH–(CH3)2),
3.62 (5H, m, N–CH–(CH3)2 + 2 · N–CH2–CH2–O),
5.00 (1H, d (broad), CH(OH)–CH2), 7.44 (5H, m,
5Ar–H), 7.55 (1H, t, Ar–Hb or Ar–Hc), 7.70 (1H, t,
Ar–Hb or Ar–Hc), 7.93 (1H, d, Ar–Ha or Ar–Hd, Jab
or Jdc 8.5 Hz), 8.10 (1H, d, Ar–Ha or Ar–Hd, Jab or
Jdc 8.3 Hz); dC (100 MHz, CDCl3): 19.29, 19.41, 20.63,
20.68, 46.12, 51.48, 53.00, 63.33, 66.39, 67.02, 124.48,
124.67, 126.91, 128.36, 128.39, 128.43, 128.67, 129.73,
129.89, 140.61, 143.08, 146.90, 159.89, 168.19; m/z 461
(M+, 5), 361 (20), 260 (40), 232 (10), 204 (25), 100 (100).
1.70 (3H, d, CH–CH3, J 6.8 Hz), 1.79 (3H, d, CH–
CH3, J 7.0 Hz), 2.24 (4H, m (broad), 2 · N–CH2–
CH2–O), 3.22 (2H, m (broad), 2 · N–CH2–CHH–O),
3.34 (2H, m (broad), 2 · N–CH2–CHH–O), 3.55 (1H,
m, N–CH–(CH3)2), 3.69 (2H, m, N–CH–(CH3)2 + 1H),
3.85 (1H, q), 4.02 (1H, m), 7.42 (5H, m, 5Ar–H), 7.57
(1H, t, Ar–Hb or Ar–Hc), 7.72 (1H, t, Ar–Hb or Ar–
Hc), 7.78 (1H, d, Ar–Ha or Ar–Hd, Jab or Jdc 8.4 Hz),
8.15 (1H, d, Ar–Ha or Ar–Hd, Jab or Jdc 8.4 Hz); dC
(100 MHz, CDCl3): 20.58, 20.67, 20.78, 22.04, 47.07,
51.73, 52.28, 65.14, 66.56, 70.75, 123.00, 124.62,
127.19, 127.52, 127.65, 128.36, 130.05, 130.08, 143.32,
143.79, 146.56, 161.00, 169.07; m/z 443 (M+, 25,
–H2O), 430 (70), 388 (100), 315 (25), 231 (50).
5.75. 3-(2-Hydroxy-1-pyrrolidin-1-yl-ethyl)-2-phenyl-
quinoline-4-carboxylic acid diisopropylamide (23c)
5.73. 3-(1-Hydroxy-2-pyrrolidin-1-yl-ethyl)-2-phenyl-
quinoline-4-carboxylic acid diisopropylamide (22c)
Using the same method as for the synthesis of b-amino
alcohol (21b), epoxide (19a) (0.2 g, 5.34 · 10ꢁ4 mol), n-
butyl lithium (0.67 mL, 1.07 · 10ꢁ3 mol) and pyrrolidine
(0.15 g, 2.14 · 10ꢁ3 mol) in THF (5 mL) were stirred for
1 h. The crude products were purified by column chro-
matography [DCM–ethyl acetate (9:1) > ethyl acetate]
and dried in vacuo (P2O5) to yield the title compound
as a 1.3:1 mixture of atropisomers. Major atropisomer
of (23c); white solid (0.11 g, 46%); Rf 0.58 [DCM–ethyl
acetate (1:1)]; Mp 179–181 ꢁC; (Found: C, 75.36%; H,
8.06%; N, 9.76%. C28H35N3O2 requires: C, 75.47%; H,
7.92%; N, 9.43%); dH (400 MHz; CDCl3): 1.03 (3H, d,
CH–CH3, J 6.5 Hz), 1.20 (3H, d, CH–CH3, J 6.5 Hz),
1.54 (4H, m (broad), 2 · N–CH2–CH2), 1.67 (3H, d,
CH–CH3, J 7.0 Hz), 1.76 (3H, d, CH–CH3, J 6.8 Hz),
2.14 (2H, m (broad), 2 · N–CHH–CH2), 2.38 (2H, m,
2 · N–CHH–CH2), 3.52 (1H, m, N–CH–(CH3)2), 3.70
(1H, m, N–CH–(CH3)2), 3.88 (2H, m), 4.16 (1H, t),
7.44 (3H, m, 3Ar–H), 7.54 (1H, t, Ar–Hb or Ar–Hc),
7.61 (2H, m, 2Ar–H), 7.71 (1H, t, Ar–Hb or Ar–Hc),
7.88 (1H, d, Ar–Ha or Ar–Hd, Jab or Jdc 8.4 Hz), 8.13
(1H, d, Ar–Ha or Ar–Hd, Jab or Jdc 8.4 Hz); m/z 427
(M+, 25, –H2O), 414 (100), 328 (20), 313 (50), 231
(40), 216 (30). Minor atropisomer of (23c); colourless
oil (0.09 g, 36%); Rf 0.17 [ethyl acetate]; dH (400 MHz;
CDCl3): 1.10 (3H, d, CH–CH3, J 6.5 Hz), 1.20 (3H, d,
CH–CH3, J 6.5 Hz), 1.39 (4H, m, 2 · N–CH2–CH2),
1.69 (3H, d, CH–CH3, J 6.7 Hz), 1.76 (3H, d, CH–
CH3, J 6.7 Hz), 2.16 (2H, m, 2 · N–CHH–CH2), 2.27
(2H, m, 2 · N–CHH–CH2), 3.59 (1H, m, N–CH–
(CH3)2), 3.70 (2H, m, N–CH–(CH3)2 + 1H), 3.94 (1H,
m), 4.19 (1H, m, (broad)), 7.34 (3H, m, 3Ar–H), 7.42
(2H, m, 2Ar–H), 7.55 (1H, t, Ar–Hb or Ar–Hc), 7.71
(1H, t, Ar–Hb or Ar–Hc), 7.78 (1H, d, Ar–Ha or Ar–
Hd, Jab or Jdc 8.4 Hz), 8.15 (1H, d, Ar–Ha or Ar–Hd,
Jab or Jdc 8.4 Hz).
Epoxide (19a) (0.2 g, 5.34 · 10ꢁ4 mol) and pyrrol-
idine (0.076 g, 1.07 · 10ꢁ3 mol) were heated at reflux in
ethanol (5 mL) for 4 h. The solvents were removed in
vacuo and the crude product was purified by column chro-
matography [DCM–ethyl acetate (19:1) > (4:1) > ethyl
acetate] and dried in vacuo (P2O5) to yield the title com-
pound (0.20 g, 82%) as a 5:1 mixture of atropisomers.
White solid; Rf 0.18 [ethyl acetate–methanol (4:1)]; Mp
164–166 ꢁC; (Found: C, 75.17%; H, 7.72%; N, 9.26%.
C28H35N3O2 requires: C, 75.47%; H, 7.92%; N,
9.43%); dH (400 MHz; CDCl3, major atropisomer):
0.99 (3H, d, CH–CH3, J 6.8 Hz), 1.20 (3H, d, CH–
CH3, J 6.8 Hz), 1.62 (3H, d, CH–CH3, J 6.8 Hz), 1.67
(4H, m (broad), 2 · N–CH2–CH2), 1.76 (3H, d, CH–
CH3, J 6.8 Hz), 2.24 (3H, m (broad), 2 · N–CHH–
CH2 + CH(OH)–CHH), 2.48 (2H, m, 2 · N–CHH–
CH2), 3.38 (1H, t, CH(OH)–CHH), 3.55 (1H, m, N–
CH–(CH3)2), 3.62 (1H, m, N–CH–(CH3)2), 4.99 (1H,
m, CH(OH)–CH2), 7.45 (5H, m, 5Ar–H), 7.54 (1H, t,
Ar–Hb or Ar–Hc), 7.70 (1H, t, Ar–Hb or Ar–Hc), 7.94
(1H, d, Ar–Ha or Ar–Hd, Jab or Jdc 8.4 Hz), 8.10 (1H,
d, Ar–Ha or Ar–Hd, Jab or Jdc 8.4 Hz); dC (100 MHz,
CDCl3): 15.33, 19.34, 19.51, 20.66, 20.72, 23.66, 46.13,
51.47, 53.35, 61.22, 65.88, 68.46, 124.55, 124.80,
126.80, 128.29, 128.79, 129.71, 129.76, 140.79, 143.00,
146.88, 160.11, 168.18; m/z 446 (M+), 411, 260, 233,
204 (60), 84 (100).
5.74. 3-(2-Hydroxy-1-morpholin-4-yl-ethyl)-2-phenyl-
quinoline-4-carboxylic acid diisopropylamide (23b)
Using the same method as for the synthesis of b-amino
alcohol (21b), epoxide (19a) (0.2 g, 5.34 · 10ꢁ4 mol), n-
butyl lithium (0.67 mL, 1.07 · 10ꢁ3 mol) and morphol-
ine (0.19 g, 2.14 · 10ꢁ3 mol) in THF (5 mL) were stirred
for 1 h. The crude product was purified by column chro-
matography [DCM–ethyl acetate > ethyl acetate] and
dried in vacuo (P2O5) to yield the title compound
(0.22 g, 90%) as a 1.25:1 mixture of atropisomers. White
solid, Rf 0.6 [DCM–ethyl acetate (1:1)]; Mp 141–143 ꢁC;
dH (400 MHz; CDCl3, major atropisomer): 1.10 (3H, d,
CH–CH3, J 6.4 Hz), 1.20 (3H, d, CH–CH3, J 6.8 Hz),
5.76. Expression and purification of human DHODH and
PfDHODH
PfDHODH and human DHODH protein expression
was carried out in SØ6745 E. coli cells (pyrD-defective
strain kindly provided by K.F. Jensen, University of
Copenhagen) transformed with the human or P. falcipa-
rum DHODH gene fused to a His6-tag in the pRSET

1966
A. N. Boa et al. / Bioorg. Med. Chem. 13 (2005) 1945–1967
expression vector (Invitrogen). Both constructs were
kindly provided by Professor J. Clardy (Harvard Medi-
cal School, USA). The over-expressed enzyme has a
molecular mass of ꢀ45 kDa and lacks a 168 amino acid
hydrophobic membrane associated domain from the
N-terminus. Cells were grown in LB medium, supple-
mented with 20 lg/mL uracil, 50 lg/mL ampicillin,
50 lg/mL methicillin, 30 lg/mL kanamycin and 34 lg/
mL chloramphenicol (Sigma, Poole, UK), to an A600
nm of 0.6–0.8, and induced with 0.8 mM isopropyl b-
D-thiogalactopyranoside (Sigma, Poole, UK) for 15–
18 h. Cells were harvested by centrifugation at 5000g
for 10 min at 4 ꢁC and then frozen at ꢁ70 ꢁC. Frozen
cell pellets were resuspended in lysis buffer (50 mM
NaH2PO4, 300 mM NaCl, 10 mM imidazole, adjusted
to pH 8.0 with NaOH) containing 15 lg/mL protease
inhibitor cocktail (Sigma, Poole, UK), consisting of
aprotinin, bestatin, E-64, leupeptin and pepstatin-A,
1 mg/mL lysozyme (Sigma, Poole, UK), and 2.5 mM
dihydroorotate (DHO, Sigma, Poole, UK). The suspen-
sion was sonicated on ice using six 20-s bursts at 200–
300 W. The lysate was then centrifuged at 15,000g for
30 min at 4 ꢁC. The supernatant recovered by centrifu-
gation was loaded onto a nickel agarose resin (Qiagen,
Crawley, UK), which had been equilibrated with wash
buffer (50 mM NaH2PO4, 300 mM NaCl, 20 mM
imidazole, adjusted to pH 8.0 with NaOH), at a ratio
of 10 mL per 1.5 mL pure matrix. The supernatant
was left to bind for 20 min at 4 ꢁC and removed follow-
ing centrifugation. Wash buffer was then added to the
matrix at a ratio of 5–10 mL per mL matrix. Following
centrifugation, the supernatant was discarded and the
process was repeated twice. Elution buffer (50 mM
NaH2PO4, 300 mM NaCl, 250 mM imidazole, adjusted
to pH 8.0 with NaOH) was then added at twice the vol-
ume of the matrix. The suspension was left for 5 min at
4 ꢁC, and the supernatant was recovered and frozen in
liquid nitrogen, before being stored at ꢁ70 ꢁC. Protein
content was quantified spectrophotometrically using
the Bradford protein assay (Bio-Rad, Hemel Hemp-
stead, UK).
5.78. Parasite growth inhibition assays
Lead compounds (5k, 12, 20a and 20b) were tested for
antiplasmodial activity against two strains of P. falcipa-
rum, NF54 3D7 and W2 mef (a chloroquine- and meflo-
3
quine-resistant strain) utilising the incorporation of H-
hypoxanthine as a marker of parasite viability. Isolates
were cultured in freshly washed pooled human O+ red
blood cells (British Transfusion Service) and hypoxan-
thine-free RPMI 1640 medium supplemented with
5.96 g/L HEPES buffer and 3.60 g/L glucose (Gibco,
Paisley, UK), 42 mL/L 5% sterile filtered sodium bicar-
bonate and 10% pooled, sterile heat-inactivated human
O+ serum (British Transfusion Service). Cultures were
incubated in low oxygen (1% oxygen, 3% carbon diox-
ide, 96% nitrogen), and maintained at 37 ꢁC. Parasite
growth inhibition assays were carried out in 96-well
microtitre plates. Parasites were aliquoted and serial
dilutions of stock compounds (10 mM in DMSO) were
added with final added haematocrit of 2.5% and para-
sitaemia of 0.5% in 1200 lL complete medium. Plates
were incubated for 48 h under low oxygen concentration
at 37 ꢁC with agitation after 24 h. 3H-hypoxanthine was
added at an activity of 1 lCi/well in 20 lL complete
medium. Plates were frozen at ꢁ20 ꢁC after 24 h. Ly-
sates were harvested with Tomtec Harvester 96ꢂ cell
harvester (Tomtec, Banbury, UK) onto Wallac 1450
MicroBetaTM glass fibre filtermats (PerkinElmerꢂ, Bea-
consfield, UK). Filters were quantified using the Wallac
MicroBetaTM 1450 Trilux liquid scintillation counter.
Inhibition curves were generated as a percentage of the
activity of control groups that received 0 lM of each
compound.
Acknowledgements
We thank the EPSRC (P.R.H.), University of Hull
(S.P.C.), Medicines for Malaria Venture, Geneva
(A.N.B. and G.A.M.) for their financial support; the
technical staff of the Department of Chemistry at the
University of Hull for their assistance, in particular
Mrs. Brenda Worthington (NMR) and Mr. David Han-
nam (MS); Martin Looker (School of Biology, Univer-
sity of Leeds) for parasite cultivation.
5.77. DHODH activity: quantification and inhibition
DHODH activity was determined colourimetrically
using 2,6-dichloroindophenol (DCIP). In this assay
DCIP acts as the final electron acceptor reoxidising
ubiquinone. Its reduction is measured spectrophoto-
metrically as a decrease in absorbance at 600 nm
(e = 18.8 mMꢁ1 cmꢁ1). All DHODH assays contained
1 lg DHODH, 0.06 mM DCIP, 150 mM KCl, 50 mM
Tris/HCl and saturating concentrations of synthetic
cofactor CoQ0 (100 lM) and dihydroorotate (DHO;
200 lM). Changes in absorbance were measured over
3 min on a SpectraMAX 340pc plate reader and data
were analysed using SOFTmaxꢂ PRO software (Mole-
cular Devices, Wokingham, UK). Compounds were
tested against PfDHODH at 10 lM. The activity of four
compounds from this initial screen, 5k, 23, 20a and 20b,
was quantified against PfDHODH and human
DHODH at concentrations between 0.01 and 200 lM.
Inhibition curves were generated as percentage of the
rate of DCIP reduction in control reactions.
References and notes
1. Fidock, D. A.; Rosenthal, P. J.; Croft, S. L.; Brun, R.;
Nwaka, S. Nat. Rev. Drug Disc. 2004, 3, 509–520.
2. Gardner, M. J.; Shallom, S. J.; Carlton, J. M.; Salzberg, S.
L.; Nene, V.; Shoaibi, A.; Ciecko, A.; Lynn, J.; Rizzo, M.;
Weaver, B.; Jarrahi, B.; Brenner, M.; Parvizi, B.; Tallon,
L.; Moazzez, A.; Granger, D.; Fujii, C.; Hansen, C.;
Pederson, J.; Feldblyum, T.; Peterson, J.; Suh, B.; Angiu-
oli, S.; Pertea, M.; Allen, J.; Selengut, J.; White, O.;
Cummings, L. M.; Smith, H. O.; Adams, M. D.; Venter, J.
C.; Carucci, D. J.; Hoffman, S. L.; Fraser, C. M. Nature
2002, 419, 531–534.
3. McRobert, L.; McConkey, G. A. Mol. Biochem. Parasitol.
2002, 119, 273–278.
4. Bartlett, R. R.; Brendel, S.; Zielinski, T.; Schorlemmer, H.
U. Transplant Proc. 1996, 28, 3074–3078; Cherwinski, H.

A. N. Boa et al. / Bioorg. Med. Chem. 13 (2005) 1945–1967
1967
M.; Cohn, R. G.; Cheung, P.; Webster, D. L.; Xu, Y. Z.;
Caulfield, J. P.; Young, J. M.; Nakano, G.; Ransom, J. T.
J. Pharmacol. Exp. Ther. 1995, 275, 1043–1049.
5. Dexter, D. L.; Hesson, D. P.; Ardecky, R. J.; Rao, G. V.;
Tippett, D. L.; Dusak, B. A.; Paull, K. D.; Plowman, J.;
DeLarco, B. M.; Narayanan, V. L.; Forbes, M. Cancer
Res. 1985, 45, 5563–5568.
6. Liu, S.; Neidhardt, E. A.; Grossman, T. H.; Ocain, T.;
Clardy, J. Struct. Fold. Des. 2000, 8, 25–33.
7. Hammond, D. J.; Burchell, J. R.; Pudney, M. Mol.
Biochem. Parasitol. 1985, 14, 97–109; Ittarat, I.; Asawa-
mahasakda, W.; Meshnick, S. R. Exp. Parasitol. 1994, 79,
50–56.
13. Baldwin, J.; Farajallah, A. M.; Malmquist, N. A.; Rathod,
P. K.; Phillips, M. A. J. Biol. Chem. 2002, 277, 41827–
41834.
14. Compounds described as having Ôno activityÕ refer to
absence of measurable activity in a preliminary screen
conducted at 10 lM inhibitor concentration. IC50 values
were only determined for compounds which showed >10%
activity at this concentration.
15. Sandmeyer, T. Helv. Chim. Acta 1919, 2, 234–239.
16. Buu-Hoi, N. P.; Royer, R.; Xuong, N. D.; Jacquignon, P.
J. Org. Chem. 1953, 18, 1209–1224.
17. Hass, H. B.; Bender, M. L. J. Am. Chem. Soc. 1949, 71,
1767–1769.
8. Kessl, J. J.; Lange, B. B.; Merbitz-Zahradnik, T.; Zwicker,
K.; Hill, P.; Meunier, B.; Palsdottir, H.; Hunte, C.;
Meshnick, S.; Trumpower, B. L. J. Biol. Chem. 2003, 278,
31312–31318.
9. Copeland, R. A.; Marcinkeviciene, J.; Haque, T. S.;
Kopcho, L. M.; Jiang, W.; Wang, K.; Ecret, L. D.;
Sizemore, C.; Amsler, K. A.; Foster, L.; Tadesse, S.;
Combs, P.; Stern, A. M.; Trainor, G. L.; Slee, A.; Rogers,
M. J.; Hobbs, F. J. Biol. Chem. 2000, 275, 33373–
33378.
10. Marcinkeviciene, J.; Rogers, M. J.; Kopcho, L.; Jiang, W.;
Wang, K.; Murphy, D. J.; Lippy, J.; Link, S.; Chung, T.
D.; Hobbs, F.; Haque, T.; Trainor, G. L.; Slee, A.; Stern,
A. M.; Copeland, R. A. Biochem. Pharmacol. 2000, 60,
339–342.
11. Batt, D. G. Exp. Opin. Ther. Patents 1999, 9, 41–54.
12. Knecht, W.; Loffler, M. Biochem. Pharmacol. 1998, 56,
1259–1264.
18. Mizutani, T.; Ema, T.; Tomita, T.; Kuroda, Y.; Ogoshi,
H. J. Am. Chem. Soc. 1994, 116, 4240–4250.
19. Snieckus, V.; Cuevas, J. C.; Sloan, C. P.; Liu, H.; Curran,
D. P. J. Am. Chem. Soc. 1990, 112, 896–898.
20. Boa, A. N.; Clark, S.; Hirst, P. R.; Westwood, R.
Tetrahedron Lett. 2003, 44, 9299–9302.
21. Growth assays were repeated to n = 5.
22. Shvekhgeimer, M.-G. A.; Kondrashova, N. N. Chem.
Heterocycl. Compd. (Engl. Transl.) 2002, 38, 253–254.
23. Hurt, D.; Clardy, J., submitted for publication.
24. Gassman, P. G.; Halweg, K. M. J. Org. Chem. 1979, 44,
184–185.
25. Pavia, M. R.; Moos, W. H.; Hershenson, F. M. J. Org.
Chem. 1990, 55, 560–564.
26. Lackey, K.; Sternbach, D. D. Synthesis 1993, 993–997.
27. Hanns, J. J. Prakt. Chem. 1932, 132, 15–19.
28. Buchman, P. G.; Howton, D. R. J. Am. Chem. Soc. 1946,
68, 2718–2719.