A short and divergent route to 2-alkenyl-4-quinolones

Article abstract of DOI:10.1016/j.tetlet.2018.08.062

2-alkenyl-4-quinolones were accessed via a high-yielding, three-step synthesis starting from 2-methyl-4-quinolones using a one-pot phosphorylation-olefination sequence as the key step and SEM as a convenient protecting group. This protocol tolerates vario

Full text of DOI:10.1016/j.tetlet.2018.08.062

Accepted Manuscript
A short and divergent route to 2-alkenyl-4-quinolones
Bernhard Lohrer, Franz Bracher
PII:
S0040-4039(18)31069-4
https://doi.org/10.1016/j.tetlet.2018.08.062
TETL 50237
DOI:
Reference:
Tetrahedron Letters
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Revised Date:
Accepted Date:
17 July 2018
19 August 2018
29 August 2018
Please cite this article as: Lohrer, B., Bracher, F., A short and divergent route to 2-alkenyl-4-quinolones, Tetrahedron
Letters (2018), doi: https://doi.org/10.1016/j.tetlet.2018.08.062
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A short and divergent route to 2-alkenyl-4-quinolones
Bernhard Lohrer and Franz Bracher*
Ludwig-Maximilians University, Department of Pharmacy – Center for Drug Research, Butenandtstr.
5-13, 81377 Munich, Germany
*Corresponding author.
e-mail address: franz.bracher@cup.uni-muenchen.de (F. Bracher)
Keywords:
4-Quinolones
Alkaloid
Olefination
Horner-Wadsworth-Emmons reaction
Abstract
Alkenyl-4-quinolones were accessed via a high-yielding, three-step synthesis starting from 2-methyl-
4-quinolones using a one-pot phosphorylation-olefination sequence as the key step and SEM as a
convenient protecting group. This protocol tolerates various functional groups and gives the target
olefins with complete (E)-selectivity.
Introduction
4-Quinolones are a scaffold of significant relevance in medicinal chemistry. Appropriately substituted
4-quinolone-3-carboxylic acids, e.g. ciprofloxacin, are among the most important fully synthetic
antibiotics.1 Furthermore, a considerable number of 4-quinolones have been isolated from biological
sources (plants like the Evodia species and microorganisms, the most prominent among these are
Pseudomonas species), and antibacterial, antiplasmodial, and cytotoxic activities have been reported
for many of them.2 These naturally occurring 4-quinolones are characterized by an alkyl or alkenyl
group at C-2, and some of them further bear a substituent at C-3. The olefinic double bond in the side-
chain can be located at a distal position (e.g. evocarpine), separated from the heterocycle by a
methylene group (e.g. burkholone), or in direct conjugation with the heterocycle (e.g. alkaloid Δ1-
pseudene-VII and some homologues3). N-Hydroxylation was detected in 4-quinolones exhibiting
strong antibiotic activity, e.g. YM-300594 and aurachin C5 (Fig. 1).
Naturally occurring 2-alkylquinolones served as lead structures for the synthesis of antimycobacterial
analogues,6 but were catapulted into the spotlight when they were identified as quorum sensing signal
molecules in Pseudomonas species, controlling the expression of virulence genes as a function of cell
population density.2a This opens a completely new option for the treatment of multidrug-resistant
Pseudomonas aeruginosa infections.7 Furthermore, N-unsubstituted 4-quinolones are useful precursors
for the synthesis of antibacterial N-hydroxy-4-quinolones8 and antiprotozoal 4-aminoquinolines.9

Figure 1. Selected 4-quinolones of pharmaceutical interest. The antibiotic ciprofloxacin and
representative 4-quinolone alkaloids bearing unsaturated side-chains: burkholone, aurachin C,
aurachin D, evocarpine, Δ1-pseudene-VII, and YM-30059.
Sophisticated methods have been developed for the industrial production of fluoroquinolone
antibiotics, among them one-pot-10 and flow-chemistry11 multi-step reactions. 4-Quinolones bearing
alkyl or aryl residues at C-2 (and/or C-3) can be prepared following established strategies.12 The most
prominent are the Conrad-Limpach synthesis (from anilines and β–ketoesters), the Camps method
(cyclization of ortho-acylaminoacetophenones) and the Niementowski reaction (from anthranilamide
and ketones as well as variants using isatoic anhydride).6,13 However, most of these methods are not or
only moderately applicable to the synthesis of 4-quinolones bearing olefinic residues, and very few
publications describe the synthesis of 2-(1-alkenyl)-4-quinolones other than styryl derivatives.6,14
A
novel rearrangement of anthranilic esters yields 2-alkenyl-3-hydroxy-4-quinolones.15 Considerable
work has been performed on the construction of 2-alkenyl-4-quinolones by the functionalization of
pre-built 2-methyl-4-quinolones. Target compounds related to burkholone (Fig. 1) bearing allylic
residues at C-2 were obtained via the cross-coupling reactions of 2-halomethyl-4-quinolones with
vinylic building blocks.16 For the synthesis of 2-(1-alkenyl)-4-quinolones, very few examples of direct
Knoevenagel-type condensations of the 2-methyl group attached to a 4-quinolone are known;17 only
aromatic aldehydes have been condensed under drastic reaction conditions (acetic anhydride, 140 or
145 °C), and the configuration of the resulting olefins is unclear. In other approaches the 2-methyl-4-
quinolones were first converted into 4-substituted (methoxy, benzyloxy) 2-methylquinolines by O-
alkylation. Deprotonation of the now CH-acidic 2-methyl group followed by reaction with diethyl
chlorophosphate gave benzylic phosphonates as building blocks for Horner-Wadsworth-Emmons
(HWE) olefinations with aldehydes.18 For 4-benzyloxy derivatives deprotection by catalytic
hydrogenation is accompanied by saturation of the 2-alkenyl residue;18b deprotection of the 4-methoxy
analogues18a has not been attempted. 4-Acetoxy-2-methylquinolines were oxidized at the methyl group
and further converted over a number of steps into quinolin-2-ylmethyl triphenylphosphonium salts,
which gave 2-alkenyl-4-quinolones after Wittig olefination and deprotection.19
Results and Discussion
In the present work we intended to develop a new general approach to N-unsubstituted 2-alkenyl-4-
quinolones, and HWE olefinations of an appropriate building block with aldehydes or ketones
appeared to provide a divergent approach to variable olefinic side-chains. However, the acidity of the
quinolone NH group impedes HWE olefinations at the stage of the 4-quinolone.20 Therefore, we
decided to convert 2-methyl-4-quinolones into O-protected 4-hydroxyquinolines to circumvent this
problem. We selected the SEM (2-(trimethylsilyl)ethoxymethyl) protecting group that had previously

found scarce attention in quinolone chemistry.21 This protecting group is stable under the anhydrous
basic conditions of a HWE reaction, and can, in a final step, be readily removed with aqueous acid or
fluoride to release the desired 4-quinolone.
The SEM protecting group was attached to 2-methylquinolone with SEM-Cl and sodium
hexamethyldisilazane (84% yield). We were aware of the ambident character of the generated
quinolone anion and supposed the SEM protecting group to be linked to the oxygen atom and not to
the nitrogen atom. This assumption was confirmed by NOE experiments and 2D-NMR spectroscopy.
Inspired by the work of Carran and co-workers22 on the synthesis of a 2-picoline-derived phosphonate,
we converted SEM-protected quinolone (2a) into phosphonate 3 by deprotonation of the acidic methyl
group using LDA, followed by trapping with diethyl chlorophosphate. Two equivalents of LDA were
required for complete conversion, since the product 3 is more acidic than the starting material 2a.
After aqueous work-up phosphonate 3 was isolated in 86% yield. HWE olefination of 3 with n-
butanal and LDA as a base gave the desired vinylquinoline 4a in 87% yield (Scheme 1). Fortunately,
this conversion of 2a could also be performed in a one-pot phosphorylation-alkenylation reaction,
since during the preparation of intermediate 3 the required deprotonated phosphonate was formed as
well. Vinylquinoline 4a was directly obtained in 87% yield from 2a (Scheme 2).
Scheme 1. Two-step olefination protocol: Generation of phosphonate 3 and subsequent Horner-
Wadswoth-Emmons reaction.
The scope of this one-pot procedure was initially investigated using various carbonyl compounds as
starting materials for the HWE reaction. The reaction worked very well (81–91% yield) with aliphatic,
aromatic, heteroaromatic and vinylogous aldehydes; even cyclohexanone gave the corresponding
alkene 4j in 87% yield (Scheme 2, Table 1, Scheme 3). The olefins 4a-i were obtained exclusively
with (E)-configuration.

Scheme 2. Synthesis of 2-alkenyl-4-quinolones 5a-i from the corresponding 2-methyl-4-quinolones
1a-e and aldehydes via a one-pot phosphorylation-alkenylation sequence.23
Table 1. Yields for the one-pot phosphorylation/HWE reaction of 2a-d with various aldehydes.
Product
R1
R2
Yield
4a
4b
4c
4d
4e
4f
H
F
OMe
CN
H
n-propyl
n-propyl
n-propyl
n-propyl
phenyl
87%
82%
80%
79%
85%
84%
85%
H
H
2-furyl
n-heptyl
4g
Scheme 3. SEM-protected 2-alkenyl-4-quinolines obtained from 1a and unsaturated aldehydes
(citronellal for 4h, cinnamaldehyde for 4i), and cyclohexylidene analogue 4j obtained in an analogous
manner utilizing cyclohexanone as the carbonyl component.
Furthermore we investigated the impact of different substituents on the benzene moiety of the
quinolone ring on the outcome of the one-pot phosphorylation-alkenylation protocol. Substituents with

electron withdrawing (fluorine, cyano) or electron donating properties (methoxy) were expected to
influence the acidity of the methyl group in intermediates 2b-d, and might thus affect the overall yield.
Fortunately, in each case the reaction proceeded very well and good yields (79–82%) of products 4b-d
were obtained (Table 1). Therefore, this method is insensitive to electronic effects, and overall has a
broad scope. Only one attempt starting with the 6-nitro analogue 2e failed, but this was due to
solubility problems.
The SEM protecting group in intermediates 4a-j was conveniently removed with tetrabutylammonium
fluoride (TBAF) to give the desired alkenylquinolones 5a-j in good to excellent yields (68–95%) with
preservation of the (E)-configuration of the vinyl groups. The overall reaction sequence is summarized
in Scheme 2.
One of the obtained products, (E)-2-(non-1-en-1-yl)quinolin-4(1H)-one (5g; also known as Pyo III),
obtained from 1a and n-octanal (64% yield over 3 steps), is an alkaloid produced by Pseudomonas
aeruginosa.3,24 This compound shows antibiotic24 and antimalarial25 properties. Previous total
syntheses of 5g using a Conrad-Limpach synthesis26 as well as a multi-step route via 2-
nonylcinchoninic acid27 yielded this alkaloid in very poor overall yields.
In conclusion, this new 3-step protocol provides a useful synthetic tool for the synthesis of the hitherto
poorly accessible 2-alkenylquinolones. The method is mild, gives high overall yields, is insensitive to
electronic effects in the starting 2-methylquinolone building block, and is applicable to the
introduction of a broad variety of vinylic groups. Due to the stereoselectivity of the HWE olefination
step, it is suitable for the controlled production of (E)-configured 2-alkenyl-4-quinolones, the
geometry typically occurring in natural products of this chemotype. This method should find broad
application in the synthesis of bioactive 2-alkenyl-4-quinolones.
Supplementary data
1
Supplementary data (experimental procedures and copies of H and 13C NMR data for all new
compounds) associated with this article can be found, in the online version, at http://dx.doi.org/........
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Highlights
• Novel three-step synthesis of poorly accessible 2-alkenylquinolones developed
• High-yielding synthesis starting from easily available 2-methylquinolones
• High functional group compatibility
• Suitable for the production of pure (E)-configured 2-alkenylquinolones
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A short and divergent route to
2-alkenyl-4-quinolones
Bernhard Lohrer and Franz Bracher