Programmed Multiple C-H Bond Functionalization of the Privileged 4-hydroxyquinoline Template

Article abstract of DOI:10.1002/chem.202100929

The introduction of substituents on bare heterocyclic scaffolds can selectively be achieved by directed C?H functionalization. However, such methods have only occasionally been used, in an iterative manner, to decorate various positions of a medicinal scaffold to build chemical libraries. We herein report the multiple, site selective, metal-catalyzed C?H functionalization of a “programmed” 4-hydroxyquinoline. This medicinally privileged template indeed possesses multiple reactive sites for diversity-oriented functionalization, of which four were targeted. The C-2 and C-8 decorations were directed by an N-oxide, before taking benefit of an O-carbamoyl protection at C-4 to perform a Fries rearrangement and install a carboxamide at C-3. This also released the carbonyl group of 4-quinolones, the ultimate directing group to functionalize position 5. Our study highlights the power of multiple C?H functionalization to generate diversity in a biologically relevant library, after showing its strong antimalarial potential.

Full text of DOI:10.1002/chem.202100929

Full Paper
doi.org/10.1002/chem.202100929
Chemistry—A European Journal
Programmed Multiple C-H Bond Functionalization of the
Privileged 4-hydroxyquinoline Template
Quentin Ronzon,[a] Wei Zhang,[a] Nicolas Casaretto,[b] Elisabeth Mouray,[c] Isabelle Florent,[c]
and Bastien Nay*[a]
Abstract: The introduction of substituents on bare hetero-
cyclic scaffolds can selectively be achieved by directed CÀ H
functionalization. However, such methods have only occa-
sionally been used, in an iterative manner, to decorate various
positions of a medicinal scaffold to build chemical libraries.
We herein report the multiple, site selective, metal-catalyzed
CÀ H functionalization of a “programmed” 4-hydroxyquinoline.
This medicinally privileged template indeed possesses multi-
ple reactive sites for diversity-oriented functionalization, of
which four were targeted. The C-2 and C-8 decorations were
directed by an N-oxide, before taking benefit of an O-
carbamoyl protection at C-4 to perform a Fries rearrangement
and install a carboxamide at C-3. This also released the
carbonyl group of 4-quinolones, the ultimate directing group
to functionalize position 5. Our study highlights the power of
multiple CÀ H functionalization to generate diversity in a
biologically relevant library, after showing its strong antima-
larial potential.
Introduction
synthesis strategies, permitting the late-stage diversification of
key pharmaceutical scaffolds.
The confluence of chemical libraries and biological screenings
holds huge promises for drug discovery. The development of
medicinally relevant compound collections can be addressed
by smart synthetic strategies,[1] while late-stage functionaliza-
tion approaches provide a useful complement for library
diversification.[2–4] Indeed, achievements empowered by transi-
tion-metal-catalysis[5] during the past two decades have
permitted the site-selective C(sp2)À H bond functionalization of
aromatic and heteroaromatic scaffolds by the use of directing
groups.[6–10] These methods allow diversity to be introduced on
medicinal targets with minimal functional group manipulations.
The concept was applied by Yu to the divergent CÀ H
functionalization of the non-steroidal anti-inflammatory drug
celecoxib, directed by a sulfonamide function present on the
molecule.[11] Several methodology-driven CÀ H functionalizations
then allowed the straightforward diversification of many
pharmaceutical and biologically relevant substrates.[12] Overall,
these approaches constitute a paradigm in diversity-oriented
However multiple CÀ H functionalizations have more rarely
been used to decorate a bare heterocyclic template in an
iterative manner, especially in the medicinal context. For
example (Figure 1, top), multiple arylations were reported on
thiazole N-oxide,[13] thiazoles,[14,15] azaindoles N-oxide,[16]
imidazole,[17] 3-methoxythiophene,[18] imidazo[1,2-a]pyrazines,[19]
or 3-acetylpyrrole.[20]
We report herein the programmed multiple CÀ H bond
functionalization of the 4-hydroxyquinoline (1) pharmacophore.
After introducing a carbamate and an N-oxide (2) for site-
selectivity, this scaffold was successively decorated at positions
8, 2, 3 and 5 (Figure 1, bottom). Importantly, 4-hydroxyquino-
line-based substrates have rarely been addressed by methodo-
logical studies, despite significant interests. Compounds pos-
sessing the privileged 4-hydroxyquinoline core or its 4-
[a] Q. Ronzon, Dr. W. Zhang, Dr. B. Nay
Laboratoire de Synthèse Organique, Ecole Polytechnique, ENSTA, CNRS
Institut Polytechnique de Paris
91128 Palaiseau Cedex (France)
E-mail: bastien.nay@polytechnique.edu
[b] Dr. N. Casaretto
Laboratoire de Chimie Moléculaire, Ecole Polytechnique, CNRS
Institut Polytechnique de Paris, 91128 Palaiseau Cedex (France)
[c] Dr. E. Mouray, Prof. Dr. I. Florent
Unité Molécules de Communication et Adaptation des Microorganismes
(MCAM, UMR7245)
Muséum national d’Histoire naturelle, CNRS, CP 52
57 rue Cuvier 75005 Paris (France)
Figure 1. Divergent multiple CÀ H bond functionalization of heterocycles.
Notes: [a] Steps can be inverted; [b] After N-oxide removal.
Supporting information for this article is available on the WWW under
https://doi.org/10.1002/chem.202100929
Chem. Eur. J. 2021, 27, 1–10
1
© 2021 Wiley-VCH GmbH
��
These are not the final page numbers!

Full Paper
doi.org/10.1002/chem.202100929
Chemistry—A European Journal
quinolone tautomer have been associated to numerous
activities,[21] especially in the field of cancer, infectious and
parasitic, or cardiovascular diseases (Figure 2).[22] Some of them
were taken as an inspiration for substituent choice during this
work.
In 2009, Fagnou and co-workers reported the selective C-2
arylation of unsubstituted quinoline N-oxide, using the Pd-
(OAc)2/P(tBu)2Me·HBF4 (1:1) catalytic system (5 mol%) in pres-
as done on electron-rich arenes in presence of cationic
ruthenium(II) and an acrylate ester.[33]
With a 4-hydroxyl group, the CÀ H functionalization could be
directed at position 5 by using [RuCl2(p-cymene)]2 or [Cp*RhCl2]2
in presence of alkynes, promoting an alkynylation[34] or an
annulation,[35,36] respectively. Alkylations were also reported in
presence of diazocarbonyl derivatives.[37] Finally, it is not
surprising that the CÀ H functionalization of the two remote
positions 6 and 7 are still poorly reported.[38] Recently Yu
described a catalyst supporting a remote directing template
allowing the functionalization of position 6.[39]
Considering this broad functionalization scope and the high
medicinal potential of the quinoline ring, we envisioned a
programmed approach for its multiple, divergent functionaliza-
tion (Figure 1, bottom). Our strategy is centered on the putative
4-hydroxyquinoline N-oxide template, which bears two direct-
ing groups for the functionalization of positions 2/8 (the N-
oxide group) and 3/5 (the 4-OH group). To avoid any
interference between the two groups and take full benefits of
the N-oxide as a directing group, the 4-hydroxyl was protected
as a carbamate, which later offered the possibility to function-
alize position 3 with a carboxamide by a Fries rearrangement.
This step would also release the 4-OH directing group to further
functionalize position 5. Overall, this approach offers a powerful
mean to generate chemical diversity, whose significance will be
demonstrated by the discovery of potent antimalarial com-
pounds.
[24]
°
ence of an aryl bromide and K2CO3 in toluene at 110 C. In
this seminal study, an excess of the N-oxide (3 equiv. relatively
to ArBr) was used to maintain high yields. Numerous studies
involving metal catalysis have demonstrated the efficiency of
the C-2 functionalization of quinoline N-oxide to introduce aryl,
alkenyl, alkyl, acyl groups or heteroatoms, using palladium,
copper and rhodium catalysts.[25] However, these methods were
rarely exemplified with an oxygenated substitution at C-4.[23a]
Alternatively, the N-oxide could serve as a directing group
to functionalize position 8.[26,27] Shibata and Matsuo reported in
2014 the alkenylation of quinoline N-oxides in presence of the
[Rh(cod)2]OTf/DM-BINAP catalytic system (10 mol%) and
diphenylalkyne.[28] This study was followed by numerous reports
describing the introduction of aryl, alkyl, alkenyl, alkynyl, allyl,
acyl, indolyl, halide, nitrogenated or other heteroatom groups
using rhodium, iridium, ruthenium, palladium, or cobalt
catalysis.[29] This field is rapidly growing but applications to 4-
oxy-substituted quinoline substrates are still rare.[29c,l]
The CÀ H functionalization of position 3 by metal catalysis
has been less frequently studied. The C-3 selective arylation of
unsubstituted quinoline was first reported by Yu, using a
Pd(OAc)2/phenanthroline catalytic system in presence of aryl Results and Discussion
bromides.[30] Alternative strategies to functionalize position 3
used of the ortho lithiation of O-carbamates followed by a Fries
rearrangement,[31] or that of O-phosphorodiamidates prior to
the electrophile addition.[32] In principle, a carbamate group
could also offer the possibility to direct an alkenylation at C-3,
4-Hydroxyquinoline (1) was first converted into N-oxides 2a
and 2b by carbamoylation in presence of diethyl and dimethyl
carbamoyl chloride, respectively, followed by N-oxidation with
m-chloroperbenzoic acid (see Scheme S1 in the supporting
information).[24,31,40] The C-2 functionalization of 2a was then
attempted in presence of bromobenzene, targeting compound
3. We tested variations of solvents, ligands, bases and the Pd/
ligand ratio, all playing a critical role in the efficiency of the
reaction. The best yield (96% by NMR) was obtained when
employing 1.2 equivalent of PhBr and a catalytic amount of
Pd(OAc)2 (10 mol%) in presence of electron-rich phosphine
ligand PCy2tBu (30 mol%, used as the HBF4 salt according to Fu
and Netherton[41]), Ag2CO3 (3 equiv) and 4 Å molecular sieves
°
(MS) in dry toluene at 100 C (Scheme 1). By contrast, under
Fagnou’s conditions (Table 1, entry 2),[24] no C-2 arylation was
observed on substrate 2a.[42] An undesired rearrangement
product
(i.e.
1-diethylcarbamyloxy-4(1H)-quinolone
2c,
Scheme 1) was instead isolated in 54% yield, resulting from the
O-carbamyl migration onto the N-oxide,[43] together with the
quinoline product (S1) resulting from the reduction of the N-
oxide (10%). A similar rearrangement was observed with 2b,
providing suitable crystals for crystallographic confirmation of
the rearranged structure (2d).[44]
Any variation from our successful condition (Table 1,
entry 1) resulted in dropping yields. The use of phenyl iodide
instead of phenyl bromide gave a satisfactory, yet lower, yield
Figure 2. Examples of decorated 4-hydroxyquinoline and 4-quinolone struc-
tures with medicinal values, taken as an inspiration for this work.[23]
Chem. Eur. J. 2021, 27, 1–10
www.chemeurj.org
2
© 2021 Wiley-VCH GmbH
��
These are not the final page numbers!

Full Paper
doi.org/10.1002/chem.202100929
Chemistry—A European Journal
that traces of water are deleterious to the reaction (entry 15).
Finally, performing the reaction under an air atmosphere
decreased the yield to 44% (entry 16).
The mechanism of the Pd-catalyzed arylation of azine N-
oxide has been thoroughly discussed in the literature. The
acetate counter-anion could have an active role as a base
during the palladium-catalyzed CÀ H activation, in a concerted
metalation-deprotonation
mechanism
hypothesized
by
Fagnou.[45] The use of a t-butylphosphinepalladium(II) complex,
by readily undergoing cyclometallation, could yet imply a
cooperative palladium catalysis involving two distinct palladium
complexes, as proposed by Hartwig on pyridine N-oxides.[46]
Furthermore, as we found that Ag(I) salts are needed to achieve
this functionalization, the silver cation could have an active role
as a halide scavenger or as a catalyst for CÀ H activation, as
discussed by Larrosa,[47] Sanford,[48] Hartwig,[49] or Houk.[50]
Scheme 1. The C-2 functionalization of substrate 2a. Structure of rearranged
products 2c and 2d, including an X-ray crystallographic representation of
2d.[44]
With these optimized conditions in hands, we evaluated the
scope of this functionalization. It could be applied to a wide
range of aryl donors (3-26, Scheme 2) including polyaromatic
(4,5), electron-rich (9-13) or electro-deficient (16-26) substrates.
Some of them were specifically chosen for biological purposes,
when incorporating aryl or long-chain alkyl substituents sharing
similarities with biologically relevant compounds (see Figure 2).
Limitations were observed with arene containing free phenols
(12), or heteroarenes like the 2-furyl (29), 2-thiophenyl (30), 4-
(N-methyl)imidazole (31) or 2-(3-hydroxy)pyridyl (32) rings
which were poorly or not reactive. However, a 2-thiazolyl
substituent (28) could be introduced in 52% yield. Ortho
substituents on phenyl rings were tolerated, except the most
electron-deficient ones in 20 (NO2), 25 (F), and 27 (CF3).
Remarkably, we were able to introduce an aryl group bearing
an O-geranyl substituent, without losing the geranyl group and
in a good yield of 78% (15a). The reaction was also possible
of 81% (entry 3). The absence of ligand or the use of bidentate
ligands (entry 4) was unable to provide any quantifiable amount
of product, while other phosphine ligands, including bulky and
electron-rich ligands like PtBu2Me (used by Fagnou[24]) or PtBu3
(used by Schneider[23a]), proved less effective than PCy2tBu
(entries 5, 6). Yields were affected by lowering the catalyst
loading (entry 7) and changing the [Pd]/PR3 ratio (entry 8).
Furthermore, we show that Ag(I) cations are essential in this
catalytic reaction, as the reaction in the presence of AgOAc
instead of Ag2CO3 still proceeds in good yields (entry 9), but
does not occur with K2CO3 (entry 10). Finally, arene solvents
were preferred, especially toluene at an optimal substrate
concentration of 0.05 M (entries 11–14). In addition, the use of
4 Å MS was necessary (3 Å MS could also be used), suggesting
Table 1. Optimization of conditions for the C-2 functionalization of substrate 2a.
Entry Deviation from best conditions
Yield
[%][a]
°
1
Pd(OAc)2 (10 mol%), PCy2tBu·HBF4 (30 mol%), Ag2CO3 (3 equiv), 4 Å MS, PhMe (0.05 M), 100 C, 48 h, under argon (best conditions, see
96
Scheme 1)
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
Fagnou’s conditions[24]: 3 equiv. of 2a, Pd(OAc)2 (5 mol%), P(tBu)2Me·HBF4 (5 mol%), K2CO3, PhMe (0.3 M), 110 C
PhI instead of PhBr
0[b]
°
81
no ligand or Phen or Bbbpy[c] instead of PCy2tBu[d]
ddpe, dppf, PCyPh2, PPh3, TFP or XantPhos[c] instead of PCy2tBu[d]
PtBu2Me,[d] PtBu3,[d] PCy3,[d] or BINAP[c] instead of PCy2tBu[d]
2 or 5 mol% instead of 10 mol% of Pd(OAc)2
Pd(OAc)2/PCy2tBu ratio: 1:1, 1:2 or 1:4 instead of 1:3
AgOAc instead of Ag2CO3
0[e]
20-33
37-66
42, 44
58, 69, 73
77
K2CO3 instead of Ag2CO3
0[e]
mesitylene, xylene instead of toluene
64, 75
21-35
38, 44
39, 55, 65
0[e]
1,2-DCE, PhCF3 or DMF[c] instead of toluene
THF, 1,4-dioxane instead of toluene
0.5 M, 0.25 M or 0.1 M instead of 0.05 M (toluene)
no 4 Å MS
air instead of argon atmosphere
44
[a] 1H NMR yields measured with dichloroethane as an internal standard. [b] Rearranged product 2c was isolated in 54% yield, accompanied by 10% of
corresponding quinoline product S1, from N-oxide reduction (see also Scheme S2 in the supporting information for details). [c] Abbreviations: BINAP: rac-2,2’-
Bis(diphenylphosphino)-1,1’-binaphthalene; 1,2-DCE: 1,2-dichloroethane; DMF: dimethylformamide; dppe: 1,2-Bis(diphenylphosphino)ethane; dppf: 1,1’-
Ferrocenediyl-bis(diphenylphosphine); Phen: 1,10-Phenanthroline; TFP: Tris-(2-furyl)phosphine; XantPhos: 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene.
[d] Used as the HBF4 salt. [e] Entry 4: No reaction; Entry 10: 2c observed in 68% yield, accompanied by 15% of N-oxide reduction; Entry 15: 2c observed in
13% yield.
Chem. Eur. J. 2021, 27, 1–10
www.chemeurj.org
3
© 2021 Wiley-VCH GmbH
��
These are not the final page numbers!

Full Paper
doi.org/10.1002/chem.202100929
Chemistry—A European Journal
Scheme 3. Trifluoroamidation at C-8: method and scope.
at room temperature. These conditions would involve the
formation of an intermediary rhodium complex A (Scheme 3)
following rhodium insertion and nitrene formation.[29n,51] After a
successful attempt on substrate 2a giving amide 34 in 77%
yield, they were applied to 2-arylated substrates bearing 4-
diethylcarbamoyloxy (11, 13, 24, 28) and 4-dimeth-
ylcarbamoyloxy (6b, 7b, 15b) substituents, affording products
(35–42). Geranylated substrate 42 was obtained with a lower
yield of 31%, as expected owing to the sensibility of this aryl
ether.
Scheme 2. C-2 functionalization of substrate 2a (NMR yields in parentheses).
Notes: [a] From 2a. [b] From 2b. [c] After [Rh]-catalyzed amidation at C-8.
when an amide function was present in position 8 (33), or a
methyl group in a multiple functionalization perspective (see
discussion below). Concerning the influence of the carbamate
group on the efficiency of the reaction, we observed that the
diethyl carbamate (2a) gave generally better yields than the
dimethyl carbamate (2b, mainly due to uncomplete conver-
sion), giving products 6a-8a or 6b-8b, respectively. The diethyl
carbamate should thus be preferred for this C-2 functionaliza-
tion.
Next, we turned our attention to the functionalization of C-
8, again directed by the N-oxide, focusing on readily affordable
Rh(III)-catalyzed amidations and methylations (Scheme 3).[29c,n]
We introduced a trifluoroacetamide group at C-8 by using Cui’s
oxidative conditions[29n] in presence of CF3CONH2 (1.2 equiv), PhI
(OAc)2 (2 equiv) and Li2CO3 (0.4 equiv), with [Cp*RhCl2]2
(4 mol%) and AgOTf (16 mol%) as a catalytic system, in 1,2-DCE
Alternatively, the methylation at C-8, expected from com-
plex intermediate B (Scheme 4), was performed in presence of
CH3BF3K (3 equiv), AgOAc (2 equiv) and a catalytic system
composed of [Cp*RhCl2]2 (10 mol%) and AgSbF6 (20 mol%) in
[29c]
°
1,2-dimethoxyethane at 65 C, according to Liu.
Substrate 3
gave mitigated results due to the undesired extra methylation
observed at the ortho position of the 2-phenyl substituent,
presumably through rhodium complex C although this assump-
tion needs further investigation (Scheme 4). An inseparable
mixture of both compounds 43 and 44 (1:2 ratio) was thus
obtained in 37% yield (Scheme 4). This result suggested that
our multiple CÀ H functionalization strategy should first target
position 8, before the arylation of position 2. Consequently, the
methylation was performed on quinoline N-oxide scaffolds 2a
Chem. Eur. J. 2021, 27, 1–10
www.chemeurj.org
4
© 2021 Wiley-VCH GmbH
��
These are not the final page numbers!

Full Paper
doi.org/10.1002/chem.202100929
Chemistry—A European Journal
Scheme 4. Methylation at C-8. Conditions: a. CH3BF3K (3 equiv), [Cp*RhCl2]2
°
(10 mol%), AgSbF6 (20 mol%), AgOAc (2 equiv), DME, 65 C, 16 h; b. ArBr
(1.1 equiv), Pd(OAc)2 (10 mol%), PCy2tBu·HBF4 (30 mol%), Ag2CO3 (3 equiv),
°
MS 4 Å, PhMe (0.05 M), 100 C, 48 h (argon atmosphere). Note: [a] HPLC ratio
(210 nm).
and 2b to furnish 8-methylquinoline derivatives 45a and 45b
in 87% and 85% yields, respectively (Scheme 4). The next
functionalization of position 2 was then performed on substrate
45b under our previously optimized palladium-catalyzed
arylation conditions, to furnish 2-aryl derivatives 46–50 in
moderate to good yields (Scheme 4, condition b). The choice of
45b instead of 45a to make this functionalization was
motivated by the next anionic Fries rearrangement, which was
reputed to work well with O-dimethylcarbamyl derivatives, but
not with their diethyl analogues.[31]
To perform the anionic ortho Fries rearrangement,[31,52,53] the
N-oxide was first reduced in presence of PCl3 (Scheme 5).
Subsequently, the lithiation of position 3 in presence of LDA
initiated the carbamoyl migration, providing quinolone prod-
ucts 51–56 in moderate to good yields (38-73%) over two
steps. Only geranyl ethers 57 and 58 were obtained in lower
yields due to substantial decomposition during the N-oxide
reduction. Gratifyingly, compound 56 (R=Me) furnished crystals
for X-ray analysis, showing the prevalence of the quinolone
form in the solid state (Figure 3).[44] Incidentally, we attempted
to use the N,N-dimethylcarbamate as a directing group for
other CÀ H functionalization at C-3, but without success despite
Scheme 5. Functionalization of position C-3 through the anionic Fries
rearrangement, to give quinolones, and hydrolysis of the carbamate group
to release 4-hydroxyquinolines. Notes: [a] Yields over two steps; [b] 52, 54
and 55 were accompanied by hydrolysed products 59, 60 and 61,
respectively.
large condition screening (lithiation of ortho position 3 followed
by addition of electrophiles,[53] or directed metal-catalyzed
arylations[33]).[54] Overall, the Fries rearrangement finally pro-
Chem. Eur. J. 2021, 27, 1–10
www.chemeurj.org
5
© 2021 Wiley-VCH GmbH
��
These are not the final page numbers!

Full Paper
doi.org/10.1002/chem.202100929
Chemistry—A European Journal
Figure 3. X-ray crystallographic structures of 56 and 76. Compound 56 co-
crystallized with a molecule of water. Compound 76 shows one disordered
methyl group on the amide nitrogen (a mask was used during the
refinement of structure 76, removing the contribution of 42 electrons from
the unit-cell content. This might correspond with a molecule of dichloro-
methane per formula unit. This disorder could not be treated in another
way).[44]
vided
a straightforward access to various substituted 4-
quinolones bearing a carboxamide moiety at position 3, which
are commonly found in biologically relevant compounds.[23c]
Most importantly, this step also released the 4-oxo directing
group that was necessary for the functionalization of position
C-5. To complete this work and increase the diversity of
compounds in view of biological investigations, the hydrolysis
of diethylcarbamates was performed to provide 4-hydroxyqui-
noline N-oxide derivatives lacking the substitution at C-3 (62–
72, Scheme 5).
Finally, an alkenylation of position C-5 was performed, in
presence of alkynes, under rhodium or ruthenium catalysis
(Scheme 6).[34–36,55] In fact, these reactions allowed an annulation
with the adjacent 4-hydroxyl group, to give fused pyran ring
systems 75–82. The reaction with diphenylacetylene (73) was
performed under the conditions defined by Patel,[35] in presence
of [RuCl2(p-cymene)]2 (5 mol%), Cu(OAc)2 (1 equiv) in 1,2-DCE at
Scheme 6. Functionalization of C-5 in presence of alkyne 73 or 74,
accompanied by the annulation with the 4-oxy group.
°
110 C, to give annulated compounds 75–78 in good yields
generally ranging from 69 to 78%, except for CF3-substituted
substrate 53 giving 76 in 57% yield. This last product gave
suitable crystals for X-ray crystallography (Figure 3).[44] Alterna-
tively, the reaction with alkyne 74 was undertaken under
conditions inspired by Shi’s work[36] in presence of [Cp*RhCl2]2
(5 mol%), AgSbF6 (20 mol%), Cu(OAc)2 (2 equiv) and KF
strategy to obtain a diverse collection of natural product- and
drug-inspired compounds. Some of them are obviously struc-
turally related to natural products like aurachin D, graveolinine,
distomadine A, and the menaquinone analogues 2-alkyl-4-
quinolones and their N-oxides, or to the heterocyclic core of
sipremevir (Figure 2). Quinolone derivatives have been de-
scribed as antimalarial compounds in many reports.[23d,e,56] More
than 50 compounds of our collection were thus engaged in a
screening against the parasite Plasmodium falciparum. First, we
measured the percentage of growth inhibition of the chlor-
oquine-resistant P. falciparum FcB1 strain by each compound at
10 μM and 1 μM (Table S24). These experiments showed that
33% of all compounds have a percentage of inhibition of the
parasite above 75% at the concentration of 10 μM, and 7% at
1 μM (57, 61, 69 and aurachin D that was available as a positive
quinolone control from a previous study[23d]). These results show
the prevalence of active compounds bearing a long lipophilic
substituent on carbon 2, and the favorable effect of the free 4-
°
(0.4 equiv) in DME at 100 C, providing lactones 79–82 in
moderate yields ranging from 33 to 59% after purification. The
selectivity was in accordance with the one described by Shi, as
imposed by the steric hindrance of the gem-dimethyl group.[36]
Interestingly these compounds are structurally related to
distomadine natural products (Figure 2).[23b] In addition, in the
absence of carboxamide substituent at position 3, the annula-
tion reactions of 4-hydroxyquinoline substrate 59 performed
well with both alkynes 73 and 74, giving products 83 and 84 in
85 and 73% yields, respectively.
Overall, we show that the multiple CÀ H bond functionaliza-
tion of a well-designed quinoline substrate is an efficient
Chem. Eur. J. 2021, 27, 1–10
www.chemeurj.org
6
© 2021 Wiley-VCH GmbH
��
These are not the final page numbers!

Full Paper
doi.org/10.1002/chem.202100929
Chemistry—A European Journal
dedicated synthetic route for each compound synthesized. Four
positions were thus successfully functionalized, applying a
programmed sequence on dedicated substrates 2a and 2b,
taking benefit of two weakly coordinating directing groups.
Two CÀ H functionalizations at C-2 and C-8 were first guided by
the N-oxide. Then, after removal of the N-oxide, an anionic
ortho Fries rearrangement of a 4-O-carbamyl moiety allowed
the functionalization of position C-3, which released the 4-oxo
group within the quinolone core. This was taken as a new
directing group for the functionalization of position C-5. Taking
into consideration the medicinal potential of this collection of
quinoline and quinolone products, they were engaged in a
biological screening against the agent of malaria, revealing
compounds (57, 69) with strong activities in the submicromolar
range. In addition, the low cytotoxicity found on human cells
revealed high selectivity indexes in favor of the antimalarial
activity, demonstrating that these compounds hold promising
properties for additional drug developments. This work shows
that the multiple functionalization strategy, associated to
substrate design, is a powerful mean to quickly generate
biologically relevant libraries.
Table 2. Mean IC50 values (μM) of selected compounds on Plasmodium
falciparum strains FcB1 and 3D7, and on the primary human fibroblast cell
line AB943 (the selectivity index, SI, was calculated by dividing the IC50
obtained from human cell line AB943 by that from P. falciparum FcB1).
Compounds
FcB1[a]
3D7[a]
AB943[b]
SI
51
55
57
61
63
64
68
69
1.10
2.15
0.07
0.24
0.32
0.34
0.65
0.08
0.09
0.048
1.32
2.92
0.16
0.32
0.47
0.75
0.92
0.12
0.21
0.011
>100
97
34.5
99
>100
38.5
63
48
>100
25
>91
45
492
412
>312
113
96
600
>1111
520
Aurachin D
Chloroquine
[a] From quadruplicate values. [b] From duplicate values.
OH group on the antimalarial activity. Based on these data, 8
promising compounds were selected for IC50 evaluation on P.
falciparum FcB1 and on the chloroquine-sensitive strain P.
falciparum 3D7 (51, 55, 57, 61, 63, 64, 68, 69, and aurachin D,
all being 4-hydroxyquinoline N-oxides or 4-quinolones). In
addition, the cytotoxicity of these compounds was evaluated
on primary human fibroblast cell line AB943. The results are Acknowledgements
shown in Table 2.
These data first demonstrate that our compounds target
both chloroquine-resistant and sensitive P. falciparum strains,
mainly at submicromolar concentrations, despite slight differ-
ences indicating a better activity against the FcB1 strain. This
observation suggests that the biological target of these
compounds could be different from that of chloroquine. Indeed,
being structural analogues of menaquinone, they are suscep-
We gratefully thank Labex CHARM3AT for funding this project
and WZ’s grant. The graduate school of Institut Polytechnique
de Paris is acknowledged for providing a PhD fellowship to QR.
We thank Sophie Bourcier and Vincent Jactel for HRMS analyses.
We thank CNRS and Ecole Polytechnique for financial supports.
tible to target the mitochondrial electron transport chain,[23d] Conflict of Interest
especially cytochrome B and type II NADH dehydrogenase.[56]
Furthermore, it is striking that compounds 57 and 69, like
aurachin D, have the best activity, at low concentrations
<0.1 μM. These compounds all share a crucial polyisoprenyl
chain. Incidentally, the 2-aryl linker in 57 and 69 may also
increase their metabolic stability.[56a] As for n-butyl-substituted
derivatives (51, 55, 61, 63, 64), they are informative on the
impact of the amide in position 3 and of the N-oxide on the
activity. The presence of the amide seems to have a strong
negative impact (51 vs. 61), while the N-oxide could have a
limited positive influence (61 vs. 63). Finally, all compounds
were poorly cytotoxic against the fibroblastic cell line AB943,
resulting in high selectivity indexes, especially for compounds
57 (SI=492), 69 (SI=600) and aurachin D (SI= >1111). At the
concentrations used to inhibit the parasites, these compounds
could therefore have a limited toxicity on the human cells.
The authors declare no conflict of interest.
Keywords: Antimalarial drugs · CÀ H bond functionalization ·
Compound library · Directing groups · Divergent synthesis
[1] O. O. Grygorenko, D. M. Volochnyuk, S. V. Ryabukhin, D. B. Judd, Chem.
Eur. J. 2020, 26, 1196–1237.
[2] K. Godula, D. Sames, Science 2006, 312, 67–72.
[3] J. Yamaguchi, A. D. Yamaguchi, K. Itami, Angew. Chem. Int. Ed. 2012, 51,
8960–9009; Angew. Chem. 2012, 124, 9092–9142.
[4] T. Cernak, K. D. Dykstra, S. Tyagarajan, P. Vachal, S. W. Krska, Chem. Soc.
Rev. 2016, 45, 546–576.
[5] P. Gandeepan, T. Müller, D. Zell, G. Cera, S. Warratz, L. Ackermann,
Chem. Rev. 2019, 119, 2192–2452.
[6] T. Brückl, R. D. Baxter, Y. Ishihara, P. S. Baran, Acc. Chem. Res. 2012, 45,
826–839.
[7] S. R. Neufeldt, M. S. Sanford, Acc. Chem. Res. 2012, 45, 936–946.
[8] N. Kuhl, M. N. Hopkinson, J. Wencel-Delord, F. Glorius, Angew. Chem. Int.
Ed. 2012, 51, 10236–10254; Angew. Chem. 2012, 124, 10382–10401.
[9] F. Zhang, D. R. Spring, Chem. Soc. Rev. 2014, 43, 6906–6919.
[10] C. Sambiagio, D. Schönbauer, R. Blieck, T. Dao-Huy, G. Pototschnig, P.
Schaaf, T. Wiesinger, M. F. Zia, J. Wencel-Delord, T. Besset, B. U. W. Maes,
M. Schnürch, Chem. Soc. Rev. 2018, 47, 6603–6743.
Conclusion
During this multiple functionalization approach, the 4-hydrox-
yquinoline scaffold was used as a valuable template to build a
substantial chemical diversity in a minimum of steps. Compara-
[11] H.-X. Dai, A. F. Stepan, M. S. Plummer, Y.-H. Zhang, J.-Q. Yu, J. Am. Chem.
Soc. 2011, 133, 7222–7228.
[12] See for example: a) M. Seki, M. Nagahama, J. Org. Chem. 2011, 76,
10198–10206; b) M. Abid Masood, E. Farrant, I. Morao, M. Bazin, M.
tively, traditional approaches would have necessitated
a
Chem. Eur. J. 2021, 27, 1–10
www.chemeurj.org
7
© 2021 Wiley-VCH GmbH
��
These are not the final page numbers!

Full Paper
doi.org/10.1002/chem.202100929
Chemistry—A European Journal
Perez, M. E. Bunnage, S.-A. Fancy, T. Peakman, Bioorg. Med. Chem. Lett.
2012, 22, 723–728; c) H. Sekizawa, K. Amaike, Y. Itoh, T. Suzuki, K. Itami,
J. Yamaguchi, ACS Med. Chem. Lett. 2014, 5, 582–586; d) M. Shang, M.-
M. Wang, T. G. Saint-Denis, M.-H. Li, H.-X. Dai, J.-Q. Yu, Angew. Chem. Int.
Ed. 2017, 56, 5317–5321; Angew. Chem. 2017, 129, 5401–5405; e) W. Ma,
H. Dong, D. Wang, L. Ackermann, Adv. Synth. Catal. 2017, 359, 966–973;
f) F. Fumagalli, S. Warratz, S.-K. Zhang, T. Rogge, C. Zhu, A. C. Stückl, L.
Ackermann, Chem. Eur. J. 2018, 24, 3984–3988; g) A. Benzai, X. Shi, F.
Derridj, T. Roisnel, H. Doucet, J.-F. Soulé, J. Org. Chem. 2019, 84, 13135–
13143.
4146; e) Y. Huang, X. Lv, H. Song, Y. Liu, Q. Wang, Chin. Chem. Lett.
2020, 31, 1572–1575; f) Alkyl: S. Han, P. Chakrasali, J. Park, H. Oh, S. Kim,
K. Kim, A. K. Pandey, S. H. Han, S. B. Han, I. S. Kim, Angew. Chem. Int. Ed.
2018, 57, 12737–12740; Angew. Chem. 2018, 130, 12919–12922; g) M. P.
Huestis, J.-P. Leclerc, R. Larouche-Gauthier, S. Aubert-Nicol, A. Yadav, K.
Sivamuthuraman, Eur. J. Org. Chem. 2021, 396–399; h) Alkenyl: R.
Sharma, R. Kumar, U. Sharma, J. Org. Chem. 2019, 84, 2786–2797; i) Allyl:
D. Kalsi, R. A. Laskar, N. Barsu, J. R. Premkumar, B. Sundararaju, Org. Lett.
2016, 18, 4198–4201; j) Alkynyl: J. Jeong, P. Patel, H. Hwang, S. Chang,
Org. Lett. 2014, 16, 4598–4601; k) Acyl: X. Chen, X. Cui, Y. Wu, Org. Lett.
2016, 18, 3722–3725; l) Amine, amide: H. Hwang, J. Kim, J. Jeong, S.
Chang, J. Am. Chem. Soc. 2014, 136, 10770–10776; m) D. Gwon, H.
Hwang, H. K. Kim, S. R. Marder, S. Chang, Chem. Eur. J. 2015, 21, 17200–
17204; n) C. You, T. Yuan, Y. Huang, C. Pi, Y. Wu, X. Cui, Org. Biomol.
Chem. 2018, 16, 4728–4733.
[13] L.-C. Campeau, M. Bertrand-Laperle, J.-P. Leclerc, E. Villemure, S.
Gorelsky, K. Fagnou, J. Am. Chem. Soc. 2008, 130, 3276–3277.
[14] F. Shibahara, E. Yamaguchi, T. Murai, J. Org. Chem. 2011, 76, 2680–2693.
[15] S. Tani, T. N. Uehara, J. Yamaguchi, K. Itami, Chem. Sci. 2014, 5, 123–135.
[16] M. P. Huestis, K. Fagnou, Org. Lett. 2009, 11, 1357–1360.
[30] M. Ye, G.-L. Gao, A. J. F. Edmunds, P. A. Worthington, J. A. Morris, J.-Q.
Yu, J. Am. Chem. Soc. 2011, 133, 19090–19093.
[31] J. M. Jacquelin, Y. Robin, A. Godard, G. Queguiner, Can. J. Chem. 1988,
66, 1135–1140.
[32] C. J. Rohbogner, S. Wirth, P. Knochel, Org. Lett. 2010, 12, 1984–1987.
[33] J. Li, C. Kornhaaß, L. Ackermann, Chem. Commun. 2012, 48, 11343–
11345.
[34] E. Tan, A. I. Konovalov, G. A. Fernández, R. Dorel, A. M. Echavarren, Org.
Lett. 2017, 19, 5561–5564.
[17] J. M. Joo, B. B. Touré, D. Sames, J. Org. Chem. 2010, 75, 4911–4920.
[18] S. Yanagisawa, K. Ueda, H. Sekizawa, K. Itami, J. Am. Chem. Soc. 2009,
131, 14622–14623.
[19] B. M. Johnson, M. P. Huestis, Eur. J. Org. Chem. 2014, 1589–1593.
[20] Y. Xu, L. Zhao, Y. Li, H. Doucet, Adv. Synth. Catal. 2013, 355, 1423–1432.
[21] For discussions on privileged structures, see: a) B. E. Evans, K. E. Rittle,
M. G. Bock, R. M. DiPardo, R. M. Freidinger, W. L. Whitter, G. F. Lundell,
D. F. Veber, P. S. Anderson, R. S. L. Chang, V. J. Lotti, D. J. Cerino, T. B.
Chen, P. J. Kling, K. A. Kunkel, J. P. Springer, J. Hirshfieldt, J. Med. Chem.
1988, 31, 2235–2246; b) M. E. Welsch, S. A. Snyder, B. R. Stockwell, Curr.
Opin. Chem. Biol. 2010, 14, 347–361.
[35] A. Banerjee, S. K. Santra, P. R. Mohanta, B. K. Patel, Org. Lett. 2015, 17,
5678–5681.
[36] G. Liao, H. Song, X.-S. Yin, B.-F. Shi, Chem. Commun. 2017, 53, 7824–
7827.
[37] K. Yan, B. Li, B. Wang, Adv. Synth. Catal. 2018, 360, 2113–2118.
[38] D. E. Stephens, O. V. Larionov, Tetrahedron 2015, 71, 8683–8716.
[39] H. Shi, Y. Lu, J. Weng, K. L. Bay, X. Chen, K. Tanaka, P. Verma, K. N. Houk,
J.-Q. Yu, Nat. Chem. 2020, 12, 399–404.
[22] For reviews on the quinoline pharmacophore, see: a) C. Mugnaini, S.
Pasquini, F. Corelli, Curr. Med. Chem. 2009, 16, 1746–1767; b) V. R.
Solomon, H. Lee, Curr. Med. Chem. 2011, 18, 1488–1508; c) R. Musiol,
Expert Opin. Drug Discovery 2017, 12, 583–597; d) T. Idowu, F. Schweizer,
Antibiotics 2017, 6, 26.
[23] a) Graveolinine: T. Rodrigues, D. Reker, J. Kunze, P. Schneider, G.
Schneider, Angew. Chem. Int. Ed. 2015, 54, 10516–10520; Angew. Chem.
2015, 127, 10662–10666; b) Distomadine A: A. N. Pearce, D. R. Appleton,
R. C. Babcock, B. R. Copp, Tetrahedron Lett. 2003, 44, 3897–3899;
c) Ciprofloxacine: T. D. M. Pham, Z. M. Ziora, M. A. T. Blaskovich, Med-
ChemComm 2019, 10, 1719–1739; d) Aurachin D: X.-W. Li, J. Herrmann,
Y. Zang, P. Grellier, S. Prado, R. Müller, B. Nay, Beilstein J. Org. Chem.
2013, 9, 1551–1558; e) Antimalarial compound: C. Pidathala, R. Amewu,
B. Pacorel, G. L. Nixon, Peter Gibbons, W. D. Hong, S. C. Leung, N. G.
Berry, R. Sharma, P. A. Stocks, A. Srivastava, A. E. Shone, S. Charoensut-
thivarakul, L. Taylor, O. Berger, A. Mbekeani, A. Hill, N. E. Fisher, A. J.
Warman, G. A. Biagini, S. A. Ward, P. M. O’Neill, J. Med. Chem. 2012, 55,
1831–1843; f) Simeprevir: T.-I Lin, O. Lenz, G. Fanning, T. Verbinnen, F.
Delouvroy, A. Scholliers, K. Vermeiren, Å. Rosenquist, M. Edlund, B.
Samuelsson, L. Vrang, H. de Kock, P. Wigerinck, P. Raboisson, K. Simmen,
Antimicrob. Agents Chemother. 2009, 53, 1377–13857.
[40] A. Woschek, M. Mahout, K. Mereiter, F. Hammerschmidt, Synthesis 2007,
10, 1517–1522.
[41] M. R. Netherton, G. C. Fu, Org. Lett. 2001, 3, 4295–4298.
[42] We checked that we could reproduce Fagnou’s functionalization of
quinoline N-oxide (3 equiv), successfully giving 89% yield of 2-phenyl-
quinoline N-oxide in our hands (ref. [24]). Our conditions worked
similarly on this substrate, giving 94% yield of product when 3 equiv. of
substrate were used (vs. 60% with 1.1 equiv), suggesting our method
could be general to quinoline substrates.
[43] This O-carbamyl rearrangement was not reported before, but Hammer-
smith and co-worker showed
a related transformation of 4-(eth-
oxycarbonyloxy)quinoline N-oxides into 1-(ethoxycarbonyloxy)-4(1H)-
quinolones (see ref. [40]). In fact, our rearrangement occurred
spontaneously in trace amounts when substrates 2a and 2b were left
in dichloromethane at room temperature for several hours. Surprisingly,
it was not observed under our C-2 functionalization conditions.
[44] Deposition numbers 2069265 (for 2d), 2042478 (for 56) 2042479 (for
76) contain the supplementary crystallographic data for this paper.
These data are provided free of charge by the joint Cambridge
Crystallographic Data Centre and Fachinformationszentrum Karlsruhe
Access Structures service.
[45] H.-Y. Sun, S. I. Gorelsky, D. R. Stuart, L.-C. Campeau, K. Fagnou, J. Am.
Chem. Soc. 2010, 75, 8180–8189.
[46] Y. Tan, F. Barrios-Landeros, J. F. Hartwig, J. Am. Chem. Soc. 2012, 134,
3683–3686.
[47] D. Whitaker, J. Burés, I. Larrosa, J. Am. Chem. Soc. 2016, 138, 8384–8387.
[48] M. D. Lotz, N. M. Camasso, A. J. Canty, M. S. Sanford, Organometallics
2017, 36, 165–171.
[49] S. Y. Lee, J. F. Hartwig, J. Am. Chem. Soc. 2016, 138, 15278–15284.
[50] K. L. Bay, Y.-F. Yang, K. N. Houk, J. Organomet. Chem. 2018, 864, 19–25.
[51] Y. Park, Y. Kim, S. Chang, Chem. Rev. 2017, 117, 9247–9301.
[52] K. Fries, G. Finck, Chem. Ber. 1908, 41, 4271–4284.
[24] L.-C. Campeau, D. R. Stuart, J.-P. Leclerc, M. Bertrand-Laperle, E.
Villemure, H.-Y. Sun, S. Lasserre, N. Guimond, M. Lecavallier, K. Fagnou,
J. Am. Chem. Soc. 2009, 131, 3291–3306.
[25] Examples: a) Aryl: H. C. Seung, J. H. Seung, S. Chang, J. Am. Chem. Soc.
2008, 130, 9254–9256; b) L. Ackermann, S. Fenner, Chem. Commun.
2011, 47, 430–432; c) Heteroaryl: F. Gosselin, S. J. Savage, N. Blaquière,
S. T. Staben, Org. Lett. 2012, 14, 862–865; d) S. Liu, C. C. Tzschucke, Eur.
J. Org. Chem. 2016, 3509–3513; e) Alkyl and alkenyl: B. Xiao, Z.-J. Liu, L.
Liu, Y. Fu, J. Am. Chem. Soc. 2013, 135, 616–619; f) J. Wu, X. Cui, L. Chen,
G. Jiang, Y. Wu, J. Am. Chem. Soc. 2009, 131, 13888–13889; g) J. Ryu,
S. H. Cho, S. Chang, Angew. Chem. Int. Ed. 2012, 51, 3677–3681; Angew.
Chem. 2012, 124, 3737–3741; h) A. Lehecq, K. Rousée, C. Schneider, V.
Levacher, C. Hoarau, X. Pannecoucke, J.-P. Bouillon, S. Couve-Bonnaire,
Eur. J. Org. Chem. 2017, 3049–3054; i) F. Roudesly, L. F. Veiros, J. Oble, G.
Poli, Org. Lett. 2018, 20, 2346–2350; j) V. V. Kouznetsov, L. Y. V. Méndez,
C. E. P. Galvis, M. C. O. Villamizar, New J. Chem. 2020, 44, 12–19;
k) Amine, amide: G. Li, C. Jia, K. Sun, Org. Lett. 2013, 15, 5198–5201;
l) G.-H. Li, D.-Q. Dong, Y. Yang, X.-Y. Yu, Z.-L. Wang, Adv. Synth. Catal.
2019, 361, 832–835.
[53] V. Snieckus, Chem. Rev. 1990, 90, 879–933.
[54] When applying the conditions previously developed for the C-2
functionalization (Table 1) to carbamate 2a, the 3-phenylquinoline
product was observed in max. 5–10% yields. We were unable to
improve this reaction.
[26] T. Iwai, M. Sawamura, ACS Catal. 2015, 5, 5031–5040.
[27] E. N. da Silva Júnior, G. A. M. Jardim, R. S. Gomes, Y.-F. Liang, L.
Ackermann, Chem. Commun. 2018, 54, 7398–7411.
[28] T. Shibata, Y. Matsuo, Adv. Synth. Catal. 2014, 356, 1516–1520.
[29] Examples a) Aryl: D. E. Stephens, J. Lakey-Beitia, A. C. Atesin, T. A. Ateşin,
G. Chavez, H. D. Arman, O. V. Larionov, ACS Catal. 2015, 5, 167–175;
b) K. Shin, S.-W. Park, S. Chang, J. Am. Chem. Soc. 2015, 137, 8584–8592;
c) B. Wang, C. Li, H. Liu, Adv. Synth. Catal. 2017, 359, 3029–3034; d) J.
Kim, K. Shin, S. Jin, D. Kim, S. Chang, J. Am. Chem. Soc. 2019, 141, 4137–
[55] W. Ma, K. Graczyk, L. Ackermann, Org. Lett. 2012, 14, 6318–6321.
Chem. Eur. J. 2021, 27, 1–10
www.chemeurj.org
8
© 2021 Wiley-VCH GmbH
��
These are not the final page numbers!

Full Paper
doi.org/10.1002/chem.202100929
Chemistry—A European Journal
[56] a) S. C. Leung, P. Gibbons, R. Amewu, G. L. Nixon, C. Pidathala, W. D.
Hong, B. Pacorel, N. G. Berry, R. Sharma, P. A. Stocks, A. Srivastava, A. E.
Shone, S. Charoensutthivarakul, L. Taylor, O. Berger, A. Mbekeani, A. Hill,
N. E. Fisher, A. J. Warman, G. A. Biagini, S. A. Ward, P. M. O’Neill, J. Med.
Chem. 2012, 55, 1844–1857; b) A. Saleh, J. Friesen, S. Baumeister, U.
Gross, W. Bohne, Antimicrob. Agents Chemother. 2007, 1217–1222; c) 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. M. Kocken,
R. N. Price, V. M. Avery, I. Angulo-Barturen, M. B. Jiménez-Díaz, 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, 57, 177ra37; d) K. D. Lane, J. Mu, J.
Lu, S. T. Windle, A. Liu, P. D. Sun, T. E. Wellems, Proc. Natl. Acad. Sci. USA
2018, 115, 6285–6290.
Manuscript received: March 14, 2021
Accepted manuscript online: April 13, 2021
Version of record online: ■■■, ■■■■
Chem. Eur. J. 2021, 27, 1–10
www.chemeurj.org
9
© 2021 Wiley-VCH GmbH
��
These are not the final page numbers!

FULL PAPER
Q. Ronzon, Dr. W. Zhang, Dr. N.
Casaretto, Dr. E. Mouray, Prof. Dr. I.
Florent, Dr. B. Nay*
1 – 10
Programmed Multiple C-H Bond
Functionalization of the Privileged 4-
hydroxyquinoline Template
The introduction of substituents on
a “programmed” 4-hydroxyquinoline
was selectively achieved by directed
multiple CÀ H functionalizations. It
could be decorated on four positions,
successively at C-8, C-2, C-3 and C-5,
three of which by using transition
metal-catalyzed reactions. Our study
highlights the power of multiple CÀ H
functionalization to generate diversity
in a biologically relevant library, after
showing its strong antimalarial
potential.