Scalable Multigram Syntheses of Antimalarial 4(1H)-Quinolones ELQ-300 and P4Q-391

Article abstract of DOI:10.1002/ejoc.201700326

Antimalarial compounds ELQ-300 and P4Q-391 are highly potent against the blood and the liver stages of the Plasmodium parasite and also possess potent transmission-blocking activity. Gram amounts of these two compounds were required for extensive assessment of in vivo efficacy, pharmacokinetics, and safety. Several deficiencies existed in the original synthetic routes of ELQ-300 and P4Q-391 including reliance on toxic heavy-metal reagents, harsh reaction conditions, and several low-yielding steps. Herein, we report the development of two alternative syntheses, which are reliable, high yielding, scalable, and have the potential to become a route of choice at process scale.

Full text of DOI:10.1002/ejoc.201700326

DOI: 10.1002/ejoc.201700326
Full Paper
Antimalarials
Scalable Multigram Syntheses of Antimalarial 4(1H)-Quinolones
ELQ-300 and P4Q-391
Niranjan K. Namelikonda, Andrii Monastyrskyi, and Roman Manetsch*
[a]
[a]
[a][‡]
Abstract: Antimalarial compounds ELQ-300 and P4Q-391 are routes of ELQ-300 and P4Q-391 including reliance on toxic
highly potent against the blood and the liver stages of the Plas- heavy-metal reagents, harsh reaction conditions, and several
modium parasite and also possess potent transmission-blocking low-yielding steps. Herein, we report the development of two
activity. Gram amounts of these two compounds were required alternative syntheses, which are reliable, high yielding, scalable,
for extensive assessment of in vivo efficacy, pharmacokinetics, and have the potential to become a route of choice at process
and safety. Several deficiencies existed in the original synthetic scale.
Introduction
3-iodo-4(1H)-quinolone 3 was obtained through regioselective
iodination of parent 4(1H)-quinolone 2 accessed through Con-
rad-Limpach cyclization of the corresponding aniline and ꢀ-keto
ester. On the other hand, the diaryl ether intermediates 8 and
4(1H)-Quinolones belong to the well-established class of
heterocyclic compounds approved by the US Food and Drug
[
1]
Administration (FDA) primarily as antibacterials. 4(1H)-Quin-
olones were also shown to be potent anticancer, antimicrobial,
and antiviral agents, with some natural products containing a
9
were synthesized by using Ullman coupling conditions. The
utilization of expensive and harsh reagents, as well as the need
for difficult chromatographic purifications, rendered this
method impractical for large-scale preparations. Two alternative
syntheses were explored in order to increase the overall yields,
decrease the number of synthetic steps, and possibly reduce
the costs.
4(1H)-quinolone scaffold inhibiting HIV integrase and thus inter-
[
2]
fering with postintegration processes. 3-Alkyl- and 3-aryl-
(1H)-quinolones have been reported to possess excellent in
4
vitro antimalarial activity in the low nanomolar range against
clinically relevant strains of Plasmodium.[3] Several research
groups, including our own, focused on developing and optimiz-
Several issues in the original synthetic route were considered
to be critical roadblocks requiring major changes to achieve
real improvements. First, the Ullmann coupling reactions used
in the preparation of diaryl ethers 8 and 9 contributed pro-
foundly to the low-to-moderate overall yield. In particular, the
synthesis of the ortho-fluoro-substituted diaryl ether 9, which
was an essential building block for the synthesis of P4Q-391,
was achieved in only 39 % yield. Consequently, an alternative
to the Ullmann coupling was critical to enhance the overall
yield and to avoid the use of stoichiometric amounts of heavy
metals. Furthermore, the isolation and purification of the inter-
mediates 4, 8 and 9 were complicated requiring both flash
chromatographic purification and recrystallizations. Introduc-
tion of the diaryl-ether moiety at the C2 position of ethyl aceto-
acetate (EAA) prior to the Conrad-Limpach cyclization would
not only simplify the purification step but also avoid the use of
the strongly acid conditions for the final deprotection step.
[
4]
ing 4(1H)-quinolone-based antimalarials leading to 4(1H)-
quinolone ELQ-300 and its analog P4Q-391 (Scheme 1), which
were shown to be orally active against all life-cycle stages of P.
[
5]
falciparum. Large amounts of ELQ-300 and P4Q-391 were
needed to extensively study in vivo efficacy, pharmacokinetics,
safety profiles, and to ultimately nominate a candidate entering
[
5]
preclinical development. Herein, we report practical and oper-
ationally simple alternatives to prepare gram-scale amounts of
ELQ-300 and P4Q-391.
For the initial lead optimization, we relied on an eight-step
synthetic route established earlier (Scheme 1).[4b,5,6] Originally,
both ELQ-300 and P4Q-391 were accessed through Suzuki–
Miyaura cross-coupling of protected iodo-substituted interme-
diate 4 with the corresponding boronic ester or acid (10 or 11)
followed by the final deprotection of resulting quinolone ether.
Finally, the conditions for the Conrad-Limpach cyclization
were sub-optimal depending on harsh reaction conditions and
[
[
a] Department of Chemistry, University of South Florida,
202 E Fowler Ave., Tampa, FL 33620, USA
‡] Present address: Department of Chemistry and Chemical Biology,
Department of Pharmaceutical Sciences, Northeastern University
[
7]
lowering the overall yields. In many instances, the cyclization
of the crude enamine intermediate, the condensation product
of the 4-chloro-3-methoxy-aniline and ethyl acetoacetate, in
high boiling solvent resulted in a dark crude product which was
difficult to purify. Optimization of the Conrad-Limpach cycliza-
tion step was considered to be a third factor adding to the
overall synthetic outcome.
4
360 Huntington Avenue, Boston, MA 02115-5000, USA
E-mail: r.manetsch@neu.edu
www.manetschlab.com
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under https://doi.org/10.1002/ejoc.201700326.
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Scheme 1. a) Na, liq. NH
benzene, reflux, then DOWTHERM A, 250 °C, 60 %; c) P4Q-391: I
DMF, EtI, room temp., 12 h, >95 %; ELQ-300: EtI, K CO , DMF, 99 %; e) P4Q-391: CuI, Cs
DIPEA, pyridine, DCM, 65 %; f) P4Q-391: nBuLi, triisopropylborate, 3 h, –78 °C then 6
DMF, 80 °C, 92 %; g) P4Q-391: Pd(PPh , 2 Na CO
3
, >95 %; b) P4Q-391: EAA, AcOH, benzene, Dean–Stark trap, reflux, overnight, then Ph
2
O, reflux, 15 min, 63 %; ELQ-300: EAA, pTsOH,
2
, Na CO
2
3
, MeOH, 90 %; ELQ-300: iodine, aq. KI, n-butylamine, DMF, 89 %; d) P4Q-391: Cs
2
CO
, 1-methyl-2-pyrrolidine, 18 h, 110 °C, 39–45 %; ELQ-300: Cu(OAc)
HCl, 18 h, 85 %; ELQ-300: Pd(dppf) Cl
, aq. K CO , DMF, 85 °C, 85 %; h) HBr, AcOH, reflux, 78–84 %.
3
,
,
2
3
2
CO
3
2
N
2
2
, bis(pinacolato)diboron, KOAc,
3
)
4
M
2
3
, DMF, 85 °C, 3 h, 68 %; ELQ-300: Pd(PPh
3
)
4
2
3
Results and Discussion
lent yields after simple flash-chromatography purification.[10] An
extra equivalent of aryl iodide 7 was easily isolated after the
arylation reaction, which could be reused to make the diaryl-
iodonium salt 13.
With the diaryl ethers 8 and 9 in hand, the arylation of EAA
was targeted (Scheme 3). Arylations of either diethyl malonate
or EAA have been reported in the literature starting from differ-
Optimization efforts first focused on alternatives to the low-
yielding metal-catalyzed Ullmann coupling reaction. Hyperva-
lent iodine compounds and diaryliodonium salts, in particular,
captured our attention as mild and selective reagents to form
the aryl-ether bond during the initial exploration. One of the
biggest advantages of hypervalent iodine compounds was the
use of metal-free reaction conditions in order to overcome cost
and toxicity issues related to the use of the organometallic rea-
gents. The corresponding diaryliodonium salt was prepared fol-
[
8]
[
4f,9]
lowing a literature procedure (Scheme 2).
Iodobenzene 7
and boronic acid 12 were treated with m-CPBA and BF ·OEt
3
2
in dichloromethane, which provided the corresponding clean,
previously reported[ iodonium salt 13 in 65 % yield as a white
solid without further purification. This straightforward reaction
was reproduced several times at a 20-gram scale. Subsequently,
the arylation of phenols 5 and 6 with iodonium salt 13 by using
potassium tert-butoxide furnished diaryl ethers 8 and 9 in excel-
4f]
2 3
Scheme 3. a) CuI (5 mol-%), Cs CO , THF, 70 °C, 2-phenylphenol, 30 h, 30 %;
Scheme 2. m-CPBA, BF
40 °C, 90 %.
3
·OEt
2
, DCM, 65 %; b) phenol 5 or 6, tBuOK, THF, 0 °C
b) 1. 3-chloro-4-methoxyaniline, AcOH, benzene, 100 °C, 24 h; 2. biphenyl
ether, 255 °C, 15 min, 35 %.
–
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ent halobenzenes.[11] Copper-mediated reactions using ligands photochemical ring-opening reactions with a choice of nucleo-
[
11b]
such as
Attempted arylations of diaryl ether 8 with EAA in the presence was first iodinated in the C5 position to provide the known 5-
of
-proline and CuI yielded trace amounts of product 14 along iodo-1,3-dioxin-4-one 17,[13] which was subsequently coupled
L
-proline or 2-phenylphenol were also documented.
philes provide a variety of useful products. 1,3-Dioxin-4-one 16
L
with an unwanted arylation of the ligand. Remarkably, the cou- with the diaryl-ether moiety. Fluoro-diaryl ether boronic acid
pling reaction between EAA and aryl iodide 8 with CuI, Cs CO , 11 was treated with iodo compound 17 in the presence of a
2
3
and 2-phenylphenol conditions provided product 14 in 30 % Pd catalyst to furnish 5-arylated 1,3-dioxin-4-one 21 in 32 %
yield, which by NMR and MS analysis was contaminated with yield. Further optimization attempts succeeded when 11 was
[
11a]
the deacylated side product as an inseparable mixture.
The converted with inexpensive KHF to its air stable and more-
2
[
14]
mixture of product 14 and deacylated side product was sub- reactive trifluoroborate 19. Based on previously reported re-
jected to the traditional Conrad-Limpach-cyclization conditions action conditions,
[
15]
the coupling between trifluoroborate 19
[
7]
to produce ELQ-300 in 30 % yield. Surprisingly, the arylation and the iodo-substituted compound 17 furnished product 21
reaction between EAA and diaryl ether 9 for the synthesis of in 70 % yield. To our delight, the coupling reaction between 17
P4Q-391 failed. Alteration of reaction conditions with catalysts, and diarylether trifluoroborate salt 18 resulted in 91 % yield.
ligands, bases, and solvents did not yield product 15, presuma- Both products 20 and 21 were easily isolated with high purity.
bly because of the ortho-fluoro substitution. Although this Thermal ring opening of aryl-substituted dioxinones 20 and 21
synthesis of the 4(1H)-quinolone was substantially more step- with ethanol in xylene provided aryl-substituted EAAs 14 and
efficient than the previously reported one (Scheme 1), the 15 in 90 % and 91 % yields, respectively.
overall yield of 5.2 % suggested room for improvement. The
Once the clean aryl-substituted EAAs 14 and 15 were ob-
formation of intermediate 14 as an inseparable mixture with tained, the Conrad-Limpach reaction was optimized. Com-
the deacylated product was also considered to be disadvanta- monly, this reaction resulted in low yields due to the lack of
geous.
product precipitation when using biphenyl ether as a solvent.
Next, an alternative approach (Scheme 4) was explored to First, EAAs 14 and 15 were refluxed with 1.5 equiv. of 4-chloro-
overcome the limitations identified in the arylation of EAA. The 3-methoxy aniline in a mixture of acetic acid and dry benzene
versatile nature of 1,3-dioxin-4-ones for generating diversified to produce the enamine intermediates. As part of the optimiza-
[
12]
building blocks is well-known and documented.
They act as tion, aniline related impurities were first removed by a rapid
protected enol forms of acetyl acetic acid whereby thermal or chromatography step under the assumption that these contam-
inations were causing problems for the precipitation of the final
4
(1H)-quinolone products. Clean enamine was then dissolved in
toluene instead of biphenyl ether and subjected to microwave
heating at 265 °C for three minutes. The 3-aryl-4(1H)-quinolones
ELQ-300 and P4Q-391 precipitated immediately, and the reac-
tion vials were stored overnight at –20 °C allowing the crystalli-
zation to complete. Gratifyingly, yields of 65 % and 81 % were
obtained for ELQ-300 and P4Q-391, respectively. The synthetic
sequence for the multigram-scale preparation of both 3-diaryl
ether-4(1H)-quinolones ELQ-300 and P4Q-391 was reproduced
and validated.
Conclusions
Two short multigram-scale syntheses of 3-aryl-4(1H)-quinolone
antimalarials have been developed providing access to either
ELQ-300 or both ELQ-300 and P4Q-391 in good yields. The
best synthetic approach of ELQ-300 and P4Q-391 was
achieved in nine total steps, of which the longest linear se-
quence consisted of eight steps. The key steps of this synthetic
approach comprise an arylation of the corresponding phenol
with the symmetrical 4-(trifluoromethoxy)phenyl iodonium salt
to furnish the biphenyl ether, followed by a straightforward
Suzuki–Miyaura coupling reaction. An esterification reaction
yielding the 2-substituted EAA intermediate, which is then fur-
ther reacted to the final products ELQ-300 or P4Q-391 in an
optimized Conrad-Limpach quinolone cyclization reaction. The
overall yield for the longest linear sequence was 22 % for P4Q-
Scheme 4. a) KHF
b) NIS, AcOH, 70 %; c) Pd
and 91 % with 18) and (4 h and 70 % with 19); d) ethanol, xylenes, 120 °C,
h, 90 %; e) 1. 4-chloro-3-methoxyaniline, AcOH, benzene, Dean–Stark trap,
reflux, 24 h; 2. toluene, 3 min, MW, 265 °C, 65 % for ELQ-300 and 81 % for
P4Q-391.
2
, MeOH, H
2
O, 70 °C, 24 h, 81 % with 11 and 70 % with 10;
2
(dba)
3
, 17, K CO , 2:1 dioxane/water, 80 °C, (75 min
2
3
5
391 and 28 % for ELQ-300. Even though the overall yields of
this synthetic approach are slightly lower in comparison to the
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6
-step longest sequence of the original, convergent synthesis, addition of p-(trifluoromethoxy) phenylboronic acid (12 g, 0.05 mol)
at 0 °C. The mixture was allowed to stir for additional 60 min at
the latter approach does not take into account the low-yielding
preparations of boronic acid or ester intermediate (yields over
steps for P4Q-391 side chain is 36 %, whereas for ELQ-300 is
room temperature and then filtered through the silica plug (110 g,
dry weight) eluting with DCM (800 mL) followed by changing the
solvent to DCM/MeOH (20:1, 1.5 L). The latter filtrate was concen-
trated and diethyl ether (200 mL) was added to induce precipita-
tion. The solid was decanted three times with cold diethyl ether
and dried at high vacuum yielding 12 g (65 % yield) of salt 13 as
2
6
0 %, Scheme 1). When directly comparing the overall yield of
halo-substituted intermediates 8 and 9, (one of the key inter-
mediates present in the original and herein presented synthe-
ses), the yields were improved from 39–45 % (up to 5 g, signifi-
cantly lower when larger scale) to 59 % (P4Q-391). More impor- (d, J = 9.1 Hz, 4 H), 7.55 (d, J = 8.5 Hz, 4 H) ppm. 13C NMR (151 MHz,
tantly, the reported approach improved the scalability and re- DMSO): δ = 150.8, 137.8, 124.1, 118.1 (q, J = 257.8 Hz), 114.4 ppm.
producibility of the synthetic sequences and allowed to scale
up the reaction of halo-substituted diarylether to up to 20 g
without any decrease in yields. Finally, the herein presented
1
white solid, m.p. 105–108 °C. H NMR (600 MHz, DMSO): δ = 8.42
19
F NMR (376 MHz, DMSO): δ = –120.85, –211.91 ppm. HRMS
–
+
(
ESI-TOF) m/z: [M – BF ] calcd. for C H F IO 448.9468, found
4 14 8 6 2
448.9462.
approach does not require any protective groups and simplifies 1-Iodo-4-[4-(trifluoromethoxy)phenoxy]benzene (8): To a sus-
purification steps due to the lack of a low-soluble 4(1H)-quin- pension of tBuOK (1.1 equiv., 6.4 g, 57.5 mmol) in THF (180 mL) was
olone moiety until the end of the synthetic sequence.
added p-iodophenol (11.5 g, 52.3 mmol) at 0 °C and the reaction
was left to stir at this temperature for 15 min. Diaryliodonium salt
1
3 (1.1 equiv., 57.5 mmol) solution in dry THF was cannulated and
the reaction was stirred in the preheated oil bath (40 °C) for 2 h
until TLC indicated complete consumption of phenol). The reaction
O at 0 °C, the organic phase was sepa-
rated and the aqueous phase was extracted with diethyl ether (3 ×
200 mL). The combined organic phases were dried (Na SO ) and
Experimental Section
(
General Information: The identity of all title compounds was veri- was then quenched with H
2
1
13
fied by H NMR and C NMR spectroscopy and by HPLC/HRMS. The
chemical purity of the titled compounds was determined by using
the following conditions: Agilent 1100 series LC/MSD with an
Eclipse XDB-C18 (4.6 mm × 100 mm, 5 μm) reversed phase column;
2
4
concentrated under reduced pressure. The crude material was puri-
fied by flash chromatography (hexanes 100 %) to give pure 17.8 g
method: = 10:90 (v/v) acetonitrile (+0.05 TFA) in H O (+0.05 TFA),
of 1-iodo-4-[4-(trifluoromethoxy)phenoxy]benzene in 90 % yield.
2
1
ramped to pure acetonitrile (+0.05 TFA) over 9 min, and holding at
pure acetonitrile for 4 min with a flow rate of 0.7 mL/min, UV de-
tector, 254 nm. The purity of each compound was ≥95 % in this
analysis. The purity of final compounds ELQ-300 and P4Q-391 was
R
f
= 0.51 (100 % hexane) H NMR (600 MHz, CDCl
3
): δ = 7.63 (d, J =
8.7 Hz, 2 H), 7.19 (d, J = 9.0 Hz, 2 H), 7.03–6.96 (m, 2 H), 6.77 (d, J =
8.7 Hz, 2 H) ppm. 13C NMR (151 MHz, CDCl
): δ = 157.0, 155.3, 145.0
(q, J = 1.91 Hz), 139.0, 122.8, 121.5, 120.6 (q, J = 257.88 Hz), 119.8,
): δ = –58.77 ppm.
3
99 %. NMR spectra were recorded at ambient temperature on a 86.8 ppm. 19F NMR (376 MHz, CDCl
>
3
4
00 or 500 MHz Varian NMR spectrometer in the solvent indicated.
2
-Fluoro-1-iodo-4-[4-(trifluoromethoxy)phenoxy]benzene (9):
1
All H NMR experiments are reported in parts per million (ppm)
relative to the signals for chloroform (δ =7.26 ppm) and dimethyl-
sulfoxide (δ =2.50 ppm). All C NMR spectra were reported in ppm
relative to the signals for chloroform (δ =77 ppm) and dimethyl-
Compound 9 was prepared according to the procedure described
for the synthesis of 1-iodo-4-[4-(trifluoromethoxy)phenoxy]benzene
1
3
(8) in 90 % yield starting from 3-fluoro-4-iodophenol (12.4 g,
1
52.3 mmol). R = 0.53 (100 % hexane). H NMR (400 MHz, CDCl ):
f
3
1
sulfoxide (δ =39.5 ppm) with H decoupled observation. Data for
δ = 7.47 (dd, J = 8.7, 7.9 Hz, 1 H), 7.21 (d, J = 8.4 Hz, 2 H), 7.05–6.99
m, 2 H), 6.76 (dd, J = 9.5, 2.7 Hz, 1 H), 6.68 (ddd, J = 8.8, 2.7, 1.1 Hz,
1
H NMR are reported as follows: chemical shift (δ ppm), multiplicity
(
(s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet),
13
1
1
1
H) ppm. C NMR (151 MHz, CDCl ): δ = 159.0 (d, J = 247.0 Hz),
3
1
3
integration and coupling constant [Hz], whereas C NMR analyses
were obtained at 101, 126, or 151 MHz and reported in terms of
chemical shift. NMR spectroscopic data was analyzed by using Mes-
tReNova Software ver. 8.1. High resolution mass spectra (HRMS)
were performed on an Agilent LC/MSD TOF system G3250AA. Iso-
mers were separated by reverse phase HPLC system (Waters Prep
57.8 (d, J = 11.04 Hz), 154.7, 145.5 (q, J = 1.78 Hz), 134.1 (d, J =
.72 Hz), 120.7 (q, J = 257.4 Hz), 120.7, 115.5 (d, J = 3.58 Hz), 107.5
19
(d, J = 25.35 Hz), 102.9 (d, J = 20.86 Hz) ppm. F NMR (376 MHz,
CDCl ): δ = –59.67, –105.03 ppm.
3
Ethyl
3-Oxo-2-{4-[4-(trifluoromethoxy)phenoxy]phenyl}-
LC 4000 system with Waters 996 Photodiode Array Detector, Agilent butanoate (Mixture with Deacylated Product) (14): An oven-
column Eclipse XDB-C18, 5 μ
eluted by using a gradient elution of 70:30 to 50:50 A/B over 30 min
at a flow rate of 5.0 mL/min, where solvent A was water and solvent
M
, 9.4 × 250 mm). Compounds were
dried Schlenk tube equipped with a magnetic stir bar and a teflon
stopcock was evacuated while hot and cooled under argon. The
tube was charged sequentially with CuI (50 mg, 5 mol-%), 2-phenyl-
B was acetonitrile. Analytical thin layer chromatography (TLC) was phenol (89 mg, 10 mol-%), Cs CO (2.53 g, 1.5 mmol), and the aryl
2 3
performed on silica gel 60 F254 pre-coated plates (0.25 mm) from
EMD Chemical Inc. and components were visualized by ultraviolet
light (254 nm). Silicycle silica gel 230–400 (particle size 40–63 μm)
mesh was used for all flash column chromatography.
iodide 8 (2.0 g, 1.0 mmol). The tube was evacuated and filled with
argon (3 times), and the teflon stopcock was replaced with a rubber
septum. Ethyl acetoacetate (1.38 g, 2.0 mmol) and anhydrous THF
(1.0 mL) was added sequentially. The septum was replaced by the
teflon stopcock under a positive pressure of argon, and the sealed
tube was placed in an oil bath preheated to 70 °C. After 30 h, the
Experimental Details
Bis(4-trifluoromethoxyphenyl)iodonium Tetrafluoroborate (13): reaction was cooled to room temperature and was then partitioned
m-CPBA (≤ 77 %, 6.59 g, 38.2 mmol) was dissolved in dry DCM between ethyl acetate (30 mL) and saturated aqueous NH Cl
115 mL). To the solution was added p-trifluoromethoxyiodo benz- (15 mL). The organic portion was dried (Na SO ), filtered through a
4
(
2
4
ene (10 g, 34.7 mmol) followed by the addition of boron trifluoride
diethyl etherate (18.3 mL) at room temperature. The resulting mix-
plug of Celite, and concentrated on a rotary evaporator. The crude
material obtained was purified by silica gel chromatography (hex-
ture was stirred at room temperature for 60 min followed by the anes/EtOAc, 10:1, R = 0.34) to obtain an inseparable mixture of
f
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keto-enol forms (1.2:1 ratio) and deacylated product ca. 20 % 1
NMR (500 MHz, CDCl ): δ = 7.51–7.00 (m, 5 H), 4.19 (q, J = 6.0 Hz,
H
255.8 Hz), 119.1, 113.3 (d, J = 3.0 Hz), 105.6 (d, J = 29.33 Hz) ppm.
F NMR (376 MHz, DMSO): δ = –121.04, –167.97, –200.85 ppm.
19
3
2
H), 3.62 (s, 2 H), 1.36 (t, J = 6.0 Hz, 3 H) ppm, in 30 % overall yield.
[
({4-[4-(Trifluoromethoxy)phenoxy]phenyl}boranylidene)-l3-
6
-Chloro-7-methoxy-2-methyl-3-{4-[4-(trifluoromethoxy)phen-
fluoranyl]potassium(III) Fluoride (18): The above compound was
prepared following the procedure described for the synthesis of
compound 19 starting from boronic acid 10 (8.2 g, 27.5 mmol) in
oxy]phenyl}quinolin-4(1H)-one (ELQ-300): (Prepared from the
mixture of corresponding 2-aryl EAA with mixture of deacylated
product). To a round-bottomed flask was added 4-chloro-3-meth-
oxyaniline (1 mmol), and mixture with 2-aryl-substituted ethyl
acetoacetate 14 (1.2 mmol), 10 mol-% of AcOH, 5 mL of benzene.
The contents were brought to reflux in a Dean–Stark trap with the
azeotropic removal of water. After 24 h the reaction was cooled to
1
70 % yield. H NMR (400 MHz, DMSO): δ = 7.36 (d, J = 8.3 Hz, 2 H),
7.31 (d, J = 9.1 Hz, 2 H), 6.99 (d, J = 9.1 Hz, 2 H), 6.81 (d, J = 7.7 Hz,
2 H) ppm. 13C NMR (101 MHz, DMSO): δ = 157.1, 153.3, 142.8 (q,
J = 1.93 Hz), 132.9 (q, J = 1.82 Hz), 122.7, 120.8 (q, J = 254.55 Hz),
118.4, 117.7 ppm. 19F NMR (376 MHz, DMSO): δ = –57.25, –138.93
room temperature and concentrated under reduced pressure. The ppm.
resulting crude enamine was dissolved in 5 mL of biphenyl ether
5
-{2-Fluoro-4-[4-(trifluoromethoxy)phenoxy]phenyl}-2,2,6-tri-
and refluxed ay 260 °C for 15 min. The precipitated solid was filtered
off and washed with excess amount of diethyl ether and dried.
Crude product was recrystallized from ethanol and a couple of
drops of DMSO to provide ELQ-300 as an off white solid in 30 %
yield.
methyl-4H-1,3-dioxin-4-one (21): To a solution of potassium tri-
fluoroborate 19 (10.6 g, 28 mmol) in degassed water (24 mL) and
1
,4-dioxane (50 mL) was added potassium carbonate (3.86 g,
28 mmol). Next, Pd (dba) (170 mg, 1.0 mol-%) was added, followed
2
3
by 2,2,6-trimethyl-5-iodo-1,3-dioxin-2-one (5 g, 18.7 mmol). The re-
action was heated at 80 °C and vigorously stirred for 4 h. After LCMS
{
(
2-Fluoro-4-[4-(trifluoromethoxy)phenoxy]phenyl}boronic Acid
11): To a solution of the 1-iodo-2-fluoro-4-[4-(trifluorometh- analysis, the reaction mixture was cooled to room temperature and
oxy)phenoxy]benzene 9 (14.8 g, 42.1 mmol) and triisopropyl borate
12.6 mL, 54.7 mmol) in dry THF (84 mL) at –78 °C was added
dropwise a 2.5 solution of n-butyllithium in hexanes (20.2 mL,
0.5 mmol). The mixture was stirred for 3 h at –78 °C, then
quenched by addition of 6 HCl (37 mL) and stirred for 18 h at
was then transferred to an extraction funnel with ethyl acetate
(50 mL), and the organic phase was removed. The aqueous phase
was extracted with ethyl acetate (3 × 25 mL), and the combined
(
M
5
organic phases were dried with MgSO , filtered, and concentrated
4
M
under reduced pressure. The crude product was purified by flash
room temperature. The mixture was partitioned between ethyl acet-
ate (650 mL) and water (650 mL), the organic phase separated and
washed with water (650 mL) and brine (650 mL), dried with sodium
sulfate, filtered and the solvent evaporated under reduced pressure.
chromatography (hexanes/EtOAc, 5:1 R = 0.50) to afford the prod-
uct 21 in 70 % yield (5.37 g). H NMR (600 MHz, DMSO): δ = 7.44
f
1
(d, J = 8.5 Hz, 2 H), 7.38 (t, J = 8.5 Hz, 1 H), 7.25–7.20 (m, 2 H), 7.01
(dd, J = 10.7, 2.4 Hz, 1 H), 6.90 (dd, J = 8.5, 2.3 Hz, 1 H), 1.91 (s, 3
H), 1.74 (s, 6 H) ppm. 13C NMR (101 MHz, DMSO): δ = 166.7, 160.5
(d, J = 245.8 Hz), 159.6, 157.6 (d, J = 11.0 Hz), 154.6, 144.3 (q, J =
1.9 Hz), 133.9 (d, J = 4.4 Hz), 123.1, 120.7, 120.1 (q, J = 255.9 Hz),
115.3 (d, J = 16.3 Hz), 114.1 (d, J = 3.2 Hz), 106.2 (d, J = 26.06 Hz),
105.8, 101.0, 24.5 (d, J = 122.89 Hz), 18.2 ppm. 19F NMR (376 MHz,
CDCl ): δ = –59.61, –112.11 ppm. HRMS calcd. for C H F O [M +
The residual solid was treated with 2
M NaOH (200 mL), stirred for
15 min, then diluted with water (800 mL) and stirred until the solids
were dissolved. The solution was filtered and the filtrate washed
with hexanes (2 × 600 mL). The aqueous layer was acidified to pH
1
with 6
water and dried under reduced pressure to give the boronic acid
1 as white solid (12.1 g, 91 %) used without further purification.
M HCl and the resulting precipitate filtered, washed with
3
20 17 4 5
+
1
H] : 413.0934, found 413.1022.
1
H NMR (600 MHz, DMSO): δ = 8.12 (s, 2 H), 7.81 (t, J = 7.7 Hz, 0.3
2
1
,2,6-Trimethyl-5-{4-[4-(trifluoromethoxy)phenoxy]phenyl}-4H-
,3-dioxin-4-one (20): The compound 20 was prepared following
H), 7.61 (t, J = 7.7 Hz, 0.7 H), 7.41 (t, J = 8.4 Hz, 2 H), 7.19 (t, J =
1
3
6
.3 Hz, 2 H), 6.87–6.75 (m, 2 H) ppm. C NMR (126 MHz, DMSO):
the procedure described for the synthesis of 21 starting from tri-
δ = 167.0 (d, J = 246.9 Hz), 159.6 (d, J = 11.4 Hz), 155.0, 144.7 (q,
J = 1.87 Hz), 137.5 (d, J = 11.3 Hz), 123.5, 121.1, 120.8, 120.5 (q, J =
fluoroborate 18 (6.24 g, 17.3 mmol) in 91 % yield. R = 0.51 (hex-
f
1
anes/EtOAc, 4:1). H NMR (400 MHz, acetone): δ = 7.39–7.34 (m, 4
2
55.92 Hz), 114.0 (d, J = 3.0 Hz), 105.9 (d, J = 28.3 Hz) ppm.
H), 7.18–7.13 (m, 2 H), 7.08–7.04 (m, 2 H), 1.98 (s, 3 H), 1.75 (s, 7 H)
{
4-[4-(Trifluoromethoxy)phenoxy]phenyl}boronic Acid (10): ppm. 13C NMR (101 MHz, DMSO): δ = 165.3, 160.3, 155.5, 143.7 (q,
Compound 10 was prepared according to the procedure described
for the synthesis of boronic acid 11 in 90 % yield from 1-iodo-4-[4-
J = 1.9 Hz), 132.5, 128.1, 123.0, 121.1 (q, J = 254.79 Hz), 119.9, 118.4,
109.6, 106.8, 105.3, 24.7, 18.4 ppm. 19F NMR (376 MHz, DMSO): δ =
+
(
trifluoromethoxy)phenoxy]benzene 8 (10 g, 26.3 mmol) as a white
–57.28 ppm. HRMS calcd. for C H F O [M + H] : 395.1100, found
2
0 17 3 5
1
solid. m.p. 101–103 °C. H NMR (500 MHz, DMSO): δ = 8.02 (s, 1 H),
395.1103.
Ethyl 2-{2-Fluoro-4-[4-(trifluoromethoxy)phenoxy]phenyl}-
-oxobutanoate (15): 2,2,6-Trimethyl-5-aryl-1,3-dioxin-4-one 21
7
2
1
2
.83 (d, J = 8.6 Hz, 2 H), 7.39 (d, J = 8.3 Hz, 2 H), 7.12 (d, J = 9.1 Hz,
1
3
H), 6.99 (d, J = 8.6 Hz, 2 H) ppm. C NMR (126 MHz, DMSO): δ =
58.0, 155.3, 143.8 (q, J = 1.9 Hz), 136.3, 123.0, 120.1, 120.1 (q, J =
3
(
6.2 g, 15.0 mmol) was taken in a reaction vessel and xylenes
1
9
55.7 Hz), 117.6 ppm. F NMR (376 MHz, DMSO): δ = –56.69 ppm.
({2-Fluoro-4-[4-(trifluoromethoxy)phenoxy]phenyl}-
boranylidene)-l3-fluoranyl]potassium(III) Fluoride (19): A
(30 mL) and ethanol (3.5 mL, 60 mmol) was added. The reaction
[
vessel was heated to 120 °C for 5 h. Then it is cooled, ethanol was
removed under reduced pressure. The crude was purified by col-
2
50 mL round-bottomed flask was filled with boronic acid 11 umn chromatography (hexanes/EtOAc, 10:1, R = 0.36) to obtain
f
(
12.5 g, 40.5 mmol), KHF2 (9.5 g, 121.6 mmol), methanol (64 mL)
the corresponding 2-substituted ethyl acetoacetate 15 in 90 % yield
1
and water (39 mL) and heated at 70 °C for 24 h. Then the reaction
mixture was cooled, filtered, washed with small amount of water
and dried to obtain 12 g of borate salt 19 (81 % yield). 1H NMR
(5.4 g) as a tautomeric mixture. H NMR (600 MHz, CDCl ): δ = 13.19
3
(s, 0.5 H), 7.36 (t, J = 8.5 Hz, 0.35 H), 7.26–7.18 (m, 2 H), 7.12–7.03
(m, 2.65 H), 6.82–6.65 (m, 2 H), 4.98 (s, 0.5 H), 4.33–4.06 (m, 2 H),
(
(
600 MHz, DMSO): δ = 7.41–7.32 (m, 3 H), 7.09–7.04 (m, 2 H), 6.65
2.24 (s, 1 H), 1.86 (s, 2 H), 1.27 (t, J = 7.1 Hz, 1 H), 1.18 (t, J = 7.1 Hz,
dd, J = 8.0, 1.7 Hz, 1 H), 6.57 (d, J = 9.6 Hz, 1 H) ppm. 13C NMR
2 H) ppm. F NMR (376 MHz, CDCl ): δ = –59.60, –111.13, –115.6
19
3
+
(151 MHz, DMSO): δ = 166.0 (d, J = 246.5 Hz), 156.2, 154.9 (d, J = ppm. HRMS (ESI-TOF) m/z: [M + H] calcd. for C H F O 401.10028,
19 16 4 5
1
0.91 Hz), 143.3, 134.5 (d, J = 16.15 Hz), 122.8, 120.1 (q, J =
found 401.1009.
Eur. J. Org. Chem. 2017, 3328–3334
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© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
Ethyl 3-Oxo-2-{4-[4-(trifluoromethoxy)phenoxy]phenyl}- 156.9 (d, J = 11.2 Hz), 154.4, 150.0, 143.8 (q, J = 2.0 Hz), 139.3, 133.8
butanoate (14): The above compound was prepared following the
procedure described for the synthesis 15 starting from compound
(d, J = 5.1 Hz), 125.3, 122.7, 120.2, 119.7 (q, J = 255.2 Hz), 119.7,
1
9
116.9, 116.5, 113.9 (d, J = 3.1 Hz), 113.4, 99.3, 56.3, 18.4 ppm.
F
2
0 (4.77 g, 12.1 mmol) in 91 % yield. R = 0.34 (hexanes/EtOAc, 10:1) NMR (376 MHz, CDCl ): δ = –52.56, –105.28 ppm. IR (neat): ν˜ = 1496,
f
3
1
–1
+
H NMR (500 MHz, CDCl ): δ = 13.12 (s, 0.4 H), 7.33 (d, J = 8.7 Hz, 1
1260, 1220, 1190, 1155 cm . HRMS (ESI-TOF) m/z: [M + H] calcd.
3
H), 7.22–7.17 (m, 2 H), 7.13 (d, J = 8.7 Hz, 1 H), 7.01 (m, 4 H), 4.68
for C H ClF NO 494.0752, found 494.0753.
24
17
4
4
(
7
s, 0.6 H), 4.29–4.15 (m, 2 H), 2.22 (s, 2 H), 1.88 (s, 1 H), 1.29 (t, J =
.2 Hz, 2 H), 1.20 (t, J = 7.1 Hz, 1 H) ppm. C NMR (101 MHz, CDCl3):
1
3
Acknowledgments
δ = 201.4, 174.2, 172.7, 168.6, 157.1, 155.9, 155.7, 155.4, 144.9, 144.7,
1
32.8, 131.1, 130.8, 128.0, 122.8, 122.7, 120.6 (q, J = 255.9 Hz), 120.2, We thank the Medicines for Malaria Venture (08/0068) for sup-
1
20.0, 119.1, 118.5, 103.7, 65.0, 61.9, 60.8, 29.0, 20.1, 14.3, 14.2 ppm.
port of initial pilot experiments and the National Institutes of
Health (R01 GM097118) for financial support to complete the
herein presented study.
19
F NMR (376 MHz, CDCl ): δ = –58.78 ppm. HRMS (ESI-TOF) m/z:
3
+
[
M + H] calcd. for C H F O 383.1101, found 383.1101.
19 17 3 5
6
-Chloro-7-methoxy-2-methyl-3-{4-[4-(trifluoromethoxy)-
phenoxy]phenyl}quinolin-4(1H)-one (ELQ-300): Compound ELQ-
Keywords: Antimalarials · Nitrogen heterocycles · Biological
activity · Synthetic methods
300 was prepared following modified Conrad-Limpach procedure.
4
-Chloro-3-methoxyaniline (2.57 g, 16.3 mmol), acetic acid
(
0.093 mL, 1.63 mmol) and ethyl 3-oxo-2-{4-[4-(trifluoromethoxy)-
phenoxy]phenyl}butanoate 14 (4.16 g, 10.9 mmol) in dry benzene
43.5 mL) were added to 100 mL round-bottomed flask to give a
[
1] a) P. Ball, J. Antimicrob. Chemother. 2000, 46 Suppl T1, 17–24; b) D. E.
King, R. Malone, S. H. Lilley, Am. Fam. Physician 2000, 61, 2741–2748; c)
J. J. Irwin, T. Sterling, M. M. Mysinger, E. S. Bolstad, R. G. Coleman, J.
Chem. Inf. Model. 2012, 52, 1757–1768.
(
brown solution. Flask was equipped with Dean–Stark trap and re-
fluxed at 110 °C for 70 h to remove all the water. After that the
reaction was cooled to room temperature and the solvent was re-
moved under reduced pressure. A quick chromatography was done
to separate the unreacted aniline. The resulting enamine was dis-
solved in 43 mL of toluene and reacted in microwave at 260 °C for
three minutes. The crashed out solid was left in the fridge overnight
to enhance crystallization. The white solid, ELQ-300, with the yield
of 65 % was filtered off and washed with excess amount of diethyl
ether and dried. No further purification was needed. 1H NMR
[
2] a) L. A. Mitscher, Chem. Rev. 2005, 105, 559–592; b) V. Cecchetti, C. Paro-
lin, S. Moro, T. Pecere, E. Filipponi, A. Calistri, O. Tabarrini, B. Gatto, M.
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Hadjeri, E. L. Peiller, C. Beney, N. Deka, M. A. Lawson, C. Dumontet, A.
Boumendjel, J. Med. Chem. 2004, 47, 4964–4970; d) J. P. Michael, Nat.
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Nat. Prod. 2014, 77, 183–187.
[3] a) D. E. Kyle, L. Gerena, K. Pitzer, M. Gettyacamin, in American Society of
Tropical Medicine and Hygiene 54th Annual Meeting, Washington, DC,
(400 MHz, DMSO): δ = 11.67 (s, 1 H), 8.00 (s, 1 H), 7.41 (d, J = 8.4 Hz,
2005; b) R. W. Winter, J. X. Kelly, M. J. Smilkstein, R. Dodean, D. Hinrichs,
2
8
H), 7.28 (d, J = 8.6 Hz, 2 H), 7.16 (d, J = 9.1 Hz, 2 H), 7.07 (d, J =
.6 Hz, 2 H), 7.06 (s, 1 H), 3.96 (s, 3 H), 2.23 (s, 3 H) ppm. 13C NMR
M. K. Riscoe, Exp. Parasitol. 2008, 118, 487–497.
[
4] a) R. M. Cross, A. Monastyrskyi, T. S. Mutka, J. N. Burrows, D. E. Kyle, R.
Manetsch, J. Med. Chem. 2010, 53, 7076–7094; b) R. M. Cross, R. Ma-
netsch, J. Org. Chem. 2010, 75, 8654–8657; c) R. M. Cross, N. K. Name-
likonda, T. S. Mutka, L. Luong, D. E. Kyle, R. Manetsch, J. Med. Chem.
(101 MHz, DMSO): δ = 173.5, 156.7, 155.8, 154.8, 146.6, 143.6, 139.6,
1
1
–
32.7, 131.5, 126.2, 123.0, 120.1 (q, J = 255.7 Hz), 119.9, 119.8, 118.7,
1
9
18.3, 118.0, 99.4, 56.4, 18.9 ppm. F NMR (376 MHz, DMSO): δ =
–
1
57.21 ppm. IR (neat): ν˜ = 1501, 1472, 1269, 1210, 1163 cm . HRMS
2011, 54, 8321–8327; d) R. Winter, J. X. Kelly, M. J. Smilkstein, D. Hinrichs,
(
ESI-TOF) m/z: [M + H]+ calcd. for C H ClF NO 476.0871, found
D. R. Koop, M. K. Riscoe, Exp. Parasitol. 2011, 127, 545–551; e) R. M. Cross,
D. L. Flanigan, A. Monastyrskyi, A. N. LaCrue, F. E. Saenz, J. R. Maignan,
T. S. Mutka, K. L. White, D. M. Shackleford, I. Bathurst, F. R. Fronczek, L.
Wojtas, W. C. Guida, S. A. Charman, J. N. Burrows, D. E. Kyle, R. Manetsch,
J. Med. Chem. 2014, 57, 8860–8879; f) A. Monastyrskyi, N. K. Name-
likonda, R. Manetsch, J. Org. Chem. 2015, 80, 2513–2520; g) R. M. Cross,
J. R. Maignan, T. S. Mutka, L. Luong, J. Sargent, D. E. Kyle, R. Manetsch, J.
Med. Chem. 2011, 54, 4399–4426; h) A. N. Lacrue, F. E. Saenz, R. M. Cross,
K. O. Udenze, A. Monastyrskyi, S. Stein, T. S. Mutka, R. Manetsch, D. E.
Kyle, Antimicrob. Agents Chemother. 2013, 57, 417–424; i) F. E. Saenz, A. N.
Lacrue, R. M. Cross, J. R. Maignan, K. Udenze, R. Manetsch, D. E. Kyle,
Antimicrob. Agents Chemother. 2013, 57, 6187–6195.
5] A. Nilsen, A. N. LaCrue, K. L. White, I. P. Forquer, R. M. Cross, J. Marfurt,
M. W. Mather, M. J. Delves, D. M. Shackleford, F. E. Saenz, J. M. Morrisey,
J. Steuten, T. Mutka, Y. Li, G. Wirjanata, E. Ryan, S. Duffy, J. X. Kelly, B. F.
Sebayang, A. M. Zeeman, R. Noviyanti, R. E. Sinden, C. H. Kocken, R. N.
Price, V. M. Avery, I. Angulo-Barturen, M. B. Jimenez-Diaz, S. Ferrer, E.
Herreros, L. M. Sanz, F. J. Gamo, I. Bathurst, J. N. Burrows, P. Siegl, R. K.
Guy, R. W. Winter, A. B. Vaidya, S. A. Charman, D. E. Kyle, R. Manetsch,
M. K. Riscoe, Sci. Transl. Med. 2013, 5, 177.
2
4
17
3
4
4
76.0889.
6
7
-Chloro-3-{2-fluoro-4-[4-(trifluoromethoxy)phenoxy]phenyl}-
-methoxy-2-methylquinolin-4(1H)-one (P4Q-391): Compound
P4Q-391 was prepared following a modified Conrad-Limpach pro-
cedure for ELQ-300. 4-chloro-3-methoxyaniline (1.10 g, 6.99 mmol),
acetic acid (0.080 mL, 1.40 mmol) and ethyl 2-{2-fluoro-4-[4-
(
6
trifluoromethoxy)phenoxy]phenyl}-3-oxobutanoate 15 (2.8 g,
.99 mmol), in dry benzene (28.0 mL) were added to 100 mL round-
bottomed flask to give a brown solution. Flask was equipped with
Dean–Stark trap and refluxed at 110 °C for 120 h to remove all the
water. In 48 h TLC showed no aniline so 0.25 eq of aniline added
and then 0.3 equiv. of aniline were added next day. After refluxing
for 5 d the reaction was cooled to room temperature and the sol-
vent was removed under reduced pressure. A quick chromatogra-
phy was done to separate the unreacted aniline. The resulting
enamine was dissolved in 28 mL of toluene and reacted in micro-
wave at 260 °C for three minutes. The reaction mixture was left in
the fridge for three days to complete crystallization. The white solid,
P4Q-391, with the yield of 81 % was filtered off and washed with
excess amount of diethyl ether and dried. No further purification
[
[
6] C. L. Yeates, J. F. Batchelor, E. C. Capon, N. J. Cheesman, M. Fry, A. T.
Hudson, M. Pudney, H. Trimming, J. Woolven, J. M. Bueno, J. Chicharro,
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7] M. Conrad, L. Limpach, Ber. Dtsch. Chem. Ges. 1887, 20, 944–948.
8] E. A. Merritt, B. Olofsson, Synthesis 2011, 517–538.
1
was needed. H NMR (400 MHz, DMSO): δ = 11.79 (s, 1 H), 7.99 (d,
[
[
[
J = 1.3 Hz, 1 H), 7.44 (d, J = 8.9 Hz, 2 H), 7.29 (t, J = 8.0 Hz, 1 H),
7
.23 (dd, J = 9.0, 1.2 Hz, 2 H), 7.08 (s, 1 H), 6.99 (d, J = 10.4 Hz, 1
9] M. Bielawski, D. Aili, B. Olofsson, J. Org. Chem. 2008, 73, 4602–4607.
13
H), 6.90 (d, J = 10.1 Hz, 1 H), 3.97 (s, 3 H), 2.20 (s, 3 H) ppm.
C
[10] N. Jalalian, E. E. Ishikawa, L. F. Silva, B. Olofsson, Org. Lett. 2011, 13, 1552–
NMR (126 MHz, DMSO): δ = 170.4, 160.2 (d, J = 246.5 Hz), 157.0,
1555.
Eur. J. Org. Chem. 2017, 3328–3334
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© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
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Received: March 3, 2017
Eur. J. Org. Chem. 2017, 3328–3334
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© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim