2,2,2-trifluoroethanol-promoted access to symmetrically 3,3-disubstituted quinoline-2,4-diones

Article abstract of DOI:10.1016/j.jfluchem.2020.109520

The unprecedented use of 2,2,2-trifluoroethanol as reaction solvent provided a facile and convenient access to symmetrically 3,3-disubstitued quinoline-2,4-diones in moderate to excellent yields and high regioselectivity, by reaction of 4-hydroxy-2-quinolones with electrophiles like methyl iodide, as well as benzyl and allyl bromides in the presence of K₂CO₃. Silver (I) oxide is required to increase the yield of the methylations.

Full text of DOI:10.1016/j.jfluchem.2020.109520

Journal Pre-proof
2,2,2-Trifluoroethanol-promoted access to symmetrically
3,3-disubstituted quinoline-2,4-diones
Marcel Manke Selvero, Gabriela N. Ledesma, Ulrich Abram,
Ernesto Schulz-Lang, Ademir Farias Morel, Enrique L. Larghi
PII:
S0022-1139(20)30071-3
DOI:
https://doi.org/10.1016/j.jfluchem.2020.109520
FLUOR 109520
Reference:
To appear in:
Journal of Fluorine Chemistry
Received Date:
Revised Date:
Accepted Date:
11 February 2020
28 March 2020
28 March 2020
Please cite this article as: Selvero MM, Ledesma GN, Abram U, Schulz-Lang E, Morel AF,
Larghi EL, 2,2,2-Trifluoroethanol-promoted access to symmetrically 3,3-disubstituted
quinoline-2,4-diones, Journal of Fluorine Chemistry (2020),
doi: https://doi.org/10.1016/j.jfluchem.2020.109520
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1
2,2,2-Trifluoroethanol-promoted access to symmetrically 3,3-disubstituted
quinoline-2,4-diones
Marcel Manke Selvero,1 Gabriela N. Ledesma,2 Ulrich Abram,3 Ernesto Schulz-
Lang,1 Ademir Farias Morel,*,1 and Enrique L. Larghi*,2
Address: 1Universidade Federal de Santa Maria, Campus Universitário, Camobi,
Santa Maria (RS) Brazil. 2Instituto de Química Rosario (IQUIR, CONICET-UNR),
Suipacha 531, Rosario (SF) Argentina. 3Institute of Chemistry and Biochemistry,
Freie Universität Berlin, Fabeckstrasse 34/36, D-14195 Berlin, Germany.
Email: Ademir F. Morel* - afmorel@base.ufsm.br. Fax: +55-55-3220-8741.
Email: Enrique L. Larghi* - larghi@iquir-conicet.gov.ar. Tel./Fax.: +54-341-437-0477.
* Corresponding authors
Graphical abstract
Highlights

2,2,2-trifluoroethanol (TFE) promotes the access to 3,3-dialkylated quinoline-2,4-
diones in moderate to high yields in a regioselective fashion.

Scope and limitations: bromo, methyl and methoxy substituents attached to the 4-
hydroxy-2-quinolone core reacted smoothly with benzyl, allyl, and prenyl bromides

2
under the assistance of K2CO3. When using MeI, Ag2O was added to boost the
reaction. Higher alkyl halides were unreactive under these conditions.
Abstract
The unprecedented use of 2,2,2-trifluoroethanol as reaction solvent provided a facile
and convenient access to symmetrically 3,3-disubstitued quinoline-2,4-diones in
moderate to excellent yields and high regioselectivity, by reaction of 4-hydroxy-2-
quinolones with electrophiles like methyl iodide, as well as benzyl and allyl bromides
in the presence of K2CO3. Silver (I) oxide is required to increase the yield of the
methylations.
Keywords: Alkylation; 3,3-disubstituted-quinoline-2,4-diones; fluorinated solvent;
heterocycles; 2,2,2-trifluoroethanol.
1. Introduction
Achieving high levels of selectivity in alkylation reactions is a strongly demanding
task when dealing with polyphilic nucleophiles. Thus, many efforts have been
devoted to find solutions to this intriguing problem [1]. Particularly, heterocyclic
systems exhibiting tautomeric equilibria have long been investigated in order to
establish regioselective alkylation conditions. In a pioneering work, Kornblum et al.
[2] studied the course of the alkylation of 2-pyridones (1) under different scenarios.
They observed that mixtures of C, N and/or O-alkyl derivatives (4a-c, Scheme 1)
were obtained, depending on the nature of the solvent, the alkylation agent and the
leaving group.
Shortly after, Hopkins and Jonak [3] re-examined the alkylation of 2-pyridones,
reaching good levels of N/O selectivity (4b,c) and excellent yields. The groups of

3
Baldwin and Wei [4] employed silver carbonate and methyl iodide in the dialkylation
of the parent 4-hydroxy-2-pyridones (2), obtaining mixtures of alkylated products
mainly composed by 4d,e (Scheme 1). More recently, the group of Mayr [5]
rationalized the ambident reactivity of the heterocyclic pyridone core from the
theoretical point of view.
Quite interestingly, however, finding a general solution for the synthetic problem
associated to the C,C-dialkylation (4f, Scheme 1) of the 4-hydroxy-2-quinolones (3)
achieving high degree of regioselectivity and good yields is a longstanding quest.
Many research groups contributed to solve this stimulating topic. Kappe et al. [6]
provided a first insight into the C,C-dialkylation of 3, obtaining the desired products 4f
by reaction with allyl bromide, BnCl and EtI in H2O or DMF; however, the yields were
variable and strongly dependent on the nature of the base, alkylation agent and
solvent. Recently, the group of Buthani [7] described a process which afforded n-
alkyl, allyl, prenyl and propargyl 3,3-disubstituted-quinoline-2,4-diones (4f, Scheme
1) in aqueous medium, in moderate to good yields. According to their findings,
formation of the desired products was accompanied by 3-monoalkyl-quinolone
derivatives (4d, Scheme 1). Interestingly, several of these substances exhibited
promising anti-HIV activity.
During our studies on the antimicrobial activity of 3,3-dibenzyl-4-hydroxyquinoline-2-
ones [8], we accessed these compunds by reduction of parent derivatives 4f. In turn,
the latter were synthesized following literature methodologies. In our hands, however,
the reported procedures gave the expected products 4f in moderate yields
complemented with variable amounts of N,C,C-trisalkylated derivatives (4g, Scheme
1), which sometime were also troublesome to separate by column chromatography.

4
A detailed literature survey revealed that most procedures for the alkylation of 4-
hydroxy-2-quinolones (3) with activated alkylating agents (C6H5CH2Br, CH3I,
CH2=CHCH2Br), provide moderate levels of chemoselectivity, affording mixtures of
O-, N- and C-alkylated by-products, depending on the nature of the solvent and base
[9]. The concomitant formation of undesired side products reflects the complex
nature of this non-trivial synthetic problem. As consequence, when several research
groups needed compounds like 4g into their synthetic work, alternative approaches
devoid of the troublesome alkylation scenario were conceived [10,11,12]. These
compounds were used as chemical precursors of clinically relevant substances, and
as structural parts of specialized catalysts for aldol, Michael and related reactions
[13,14].
Therefore, moved by the selectivity limitations of the available alternatives for the 3,3-
dialkylation of the heterocyclic core 3, we decided to develop an alternative method
toward quinoline-2,4-dione derivatives (4f).
2. Results and Discussion
Our efforts oriented to C,C-dialkylate 5a commenced by adapting the conditions of
Kornblum et al. [15] to our synthetic problem. Initially, several solvents and bases
were examined, employing BnBr as alkylating agent (Table 1). A model with MeI was
also prepared, due to the interesting synthetic and pharmacological applications of
the 3,3-dimethyl derivatives [Error! Bookmark not defined.c,Error! Bookmark not
defined.,] [16].
In a biphasic PhH/H2O medium, using NaOH or K2CO3 as bases and different BnBr
molar ratios, we were able to cleanly obtain the desired product 6a in up to 85% yield
(entries 1-3). However, repeating the transformation with MeI did not met with the
same success. No reaction was observed in the presence of KOH (entry 4), whereas

5
the use of K2CO3 as base afforded a meagre 17% yield of 3,3-dimethylated product
7a (entry 5).
Unexpectedly, when benzene was replaced with the more convenient toluene, the
yield of 6a dropped to 40%, and the concomitant formation of the tris-benzyl
derivative 8 was observed (entry 6) [Error! Bookmark not defined.]. Even worse,
when MeCN and K2CO3 were employed, derivatives 8 and 9 were detected (entries 7
and 8) as the major components of reactions after using BnBr and MeI as
electrophiles, respectively [14a].
Further, the methylation in acetone employing K2CO3 furnished the desired product
7a along with polyalkylated derivatives (entry 9), consistent with the observation of
Reisch [17]. Other examined solvents (DMF, EtOH, dioxane) mostly afforded
complex mixtures or partial reaction, enabling the recovery of the starting quinolone.
After re-examining the conditions of Kornblum and recently rationalized by Adlington
[15a,b], we focused our attention on 2,2,2-trifluoroethanol (TFE) as a more suitable
reaction medium [18]. This solvent demonstrated to promote the C-alkylation of
phenols and naphthols, instead of functionalization of the more reactive OH group, by
blocking the oxygen atom through selective hydrogen bonding [15b]. Moreover, this
solvent showed to be particularly useful in promoting otherwise difficult or poorly
selective reactions [19].
The unique properties of TFE, including its high ionizing power and relatively non-
nucleophilic character (when compared with water and alkanols) facilitate ionic
reactions and provide better selectivity for the alkylation with external electrophiles,
despite the competing solvolysis of the latter [20].
Therefore, when quinolone 5a was treated with BnBr in the presence of CF3CH2ONa,
the desired product 6a was obtained in 78% yield after 22 h at room temperature
(entry 10). Fortunately, replacement of this base with the inexpensive K2CO3

6
consistently provided 6a in 97% yield, at the expense of the need to stir the mixture
at 60 °C during 17 h (entry 11).
Unexpectedly, however, application of the best conditions found for dibenzylation
(entry 11) to the gem-dimethylation reaction met with failure, and only 17% yield of
product 7a was attained (entry 12). Further, the reaction in the presence of KOH as
base had no better fate, giving 7a in 14% yield (entry 13).
These observations suggested that the reactivity of MeI required an additional fine
tuning to more efficiently furnish the expected product. Hence, it was hoped that the
addition of silver salts would suffice to enhance the system reactivity [21]. These
compounds weaken the C-Hal bond during the nucleophilic displacement, and
concomitantly form highly insoluble silver halides, which drive the reaction to
completion. We have previously used this concept for the preparation of 2,4-dialkoxy
quinolines [22]. In addition, despite it has found scattered use in the chemistry of
quinolones, this strategy was also employed for the synthesis of sterically hindered
heterocycles [23].
Therefore, Ag2CO3 was added to the reaction mixture, affording a dissapointing 18%
yield of the product (entry 14). Delightfully, when the reaction mixture was
supplemented with Ag2O the 3,3-dimethylquinolone 7a was obtained in a moderate
52% yield, after stirring the reaction mixture at room temperature during 12 h (entry
15).
With the optimized conditions in hand, the scope and limitations of the procedure
were explored. Several 4-hydroxy-2-quinolones (5a-e) were tested (Table 2),
affording benzylated products 6a-e in good to excellent yields (entries 1-5).
The scope of the optimized methylation conditions was also tested with compounds
5a-e, obtaining products 7a-e in 17-52% yield (entries 6-10). In addition, we were

7
glad to observe the formation of products 10a-e in moderate to good yields (52-62%)
when the benzylation protocol was extended to reactions using allyl bromide as
alkylating agent (entries 11-15). Further, prenyl bromide reacted smoothly with 5a to
afford the 3,3-diprenyl quinolone 11 in 47% yield (entry 16).
Finally, when the alkylation reaction was tested with the less reactive n-propyl iodide,
and despite the transformation was performed in the presence of Ag2O, only 8% yield
of the desired product 12 was obtained, accompanied by unreacted starting material
(> 80%) [Error! Bookmark not defined.a]. Further, alkyl halides with longer carbon
chains proved to be essentially unreactive, establishing a limitation to this protocol.
The structures of the different heterocyclic products were assessed by NMR and IR
spectroscopy. In addition, the solid state structure of the newly synthesized quinolone
6c was also characterized by single-crystal X-ray diffraction [24], confirming its
assignment. Compound 6c crystallizes in the monoclinic space group P 21/c, with
four molecules per unit cell (Figure 1) without molecules of solvent.
3. Conclusion
In summary, the unprecedented use of 2,2,2-trifluoroethanol as a unique solvent for
the synthesis of 3,3-disubstituted quinoline-2,4-diones by the selective dialkylation of
the readily available 4-hydroxy-2-quinolones in the presence of K2CO3 as base, was
reported. The transformation was optimized for benzylation and methylation
reactions, and its scope and limitations were studied.
The procedure selectively gave moderate to excellent yields of the symmetrically
C,C-dialkylated products, being advantageous because of the use of a more benign
solvent, mild reaction conditions and an economically accessible base, as well as the
highly stable silver(I) oxide, as promoter for the methylation.

8
The general applicability of the transformation, which is able to accommodate a
variety of substituents and substitution patterns, turns this reaction into a convenient
and complementary alternative to other methodologies oriented toward 3,3-
disubstituted-quinoline-2,4-diones.
4. Experimental
4.1. General remark
The reactions were performed under dry argon atmosphere, using oven dried
glassware. Benzyl bromide, allyl bromide and MeI were distilled prior to use [25].
K2CO3 was oven-dried before use. The solvents (TFE, MeCN, Me2CO and PhH)
were of PA grade and were used as received. The 4-hydroxy-2-quinolones were
prepared as described by Ferretti et al. [8].
The reactions were monitored by TLC (Merck's silica gel 60 GF254) employing
mixtures of hexanes/EtOAc for elution. The chromatographic spots were visualized
by exposure to UV light (254 and 365 nm) and spraying with ethanolic p-
anisaldehyde/sulfuric acid reagent, followed by careful heating to improve selectivity.
The column chromatographies were executed on silica gel (230-400 mesh), eluting
with mixtures of hexanes and EtOAc of increasing polarity.
4.2. Equipment
The melting points (uncorrected) were measured on a Microquímica MQAPF-301
hot-stage microscope and are informed uncorrected. The FT-IR spectra were
recorded on Perkin-Elmer 1310 or Bruker IFS-28 spectrophotometers as solid
dispersions in KBr compressed disks (solid samples) or as thin films held between
NaCl cells (oily samples).

9
The NMR spectroscopic data were recorded in CDCl3 unless otherwise stated, with a
Bruker DPX-200 instrument. Chemical shifts are reported in ppm on the  scale and
the solvent residual signals of CDCl3 ( = 7.26 and 77.0 ppm for 1H and 13C NMR,
respectively) were used as internal standard. Multiplicities are abbreviated as follows:
s = singlet, sb = broad singlet, d = doublet, dd = doublet of doublets, t = triplet, m =
multiplet. Signal assignments were carried out based on 1H, 13C, DEPT, HSQC,
HMBC and COSY spectra. The assigned resonances marked with “*” or “#” are
interchangeable. The magnitude of the coupling constant (J) values are given in
Hertz.
HRMS were obtained with a Bruker MicroTOF-Q II instrument (UMYMFOR, Buenos
Aires, Argentina) and a Bruker BioApex spectrometer (FAB technique, at 70 eV) from
the Institut of Plant Biochemistry, Halle-Saale, Germany.
The X-ray diffraction data were collected on an automated single crystal CAD4
(Enraf-Nonius, Delft, Netherlands) diffractometer with Mo Kα radiation (FU Berlin,
Germany). The structure was solved by direct methods using SHELXS-97 and
refined with SHELXL-97 on F2 using anisotropic temperature parameters for all non-
hydrogen atoms [26].Hydrogen atom positions were calculated starting from idealized
positions, and the molecular structures were designed with DIAMOND [27]. Table S1
contains crystal data and more details of the data collections and refinements.
4.3. General procedure for the C,C-dialkylation of 4-hydroxy-2-quinolones
To the appropriate 4-hydroxy-2-quinolone (1.0 mmol), K2CO3 (6.0 mmol) and TFE
(8.0 mL) were added. The slurry was magnetically stirred until partial dissolution of
the quinolone. After this, the halide (6.0 mmol; 12.0 mmol in case of MeI) was added,
the system was capped with a septum and stirred under argon atmosphere at 60 °C
until consumption of starting material. For the methylation, Ag2O (2.0 mmol) was

10
added before the MeI. The mixture was stirred at room temperature for 12h,
protected from light with an aluminum foil. Then, the solvent was recovered by
careful distillation at atmospheric pressure, and the resulting solids were suspended
in EtOAc (10 mL). The solids were filtered under reduced pressure through a Celite
pad and washed with small portions of EtOAc (4  2 mL). The combined liquids were
concentrated in vacuum and the residue was purified by column chromatography.
4.4. Characterization of the products
(6a) [6b]: Colorless solid; mp: 187-188 °C. IR (KBr) ν; 3180, 3066, 2937, 1692, 1657,
1605, 1599, 1489, 1391, 1301, 770, 701, 500, 443 cm-1. 1H NMR (200 MHz, CDCl3):
 9.47 (sb, 1H, H-1), 7.88 (dd, J = 7.8, 1.5, 1H, H-5), 7.29-6.93 (m, 12H, C6H5CH2, H-
6, 7), 6.55 (d, J = 8.0, 1H, H-8), 3.51 (d, J = 12.8, 2H, C6H5CH2), 3.43 (d, J = 12.8,
2H, C6H5CH2). 13C NMR (50 MHz, CDCl3):  197.1 (C-4), 173.7 (C-2), 140.3 (C-5a),
135.8 (C-7), 135.6 (2C, C-ipso, C6H5CH2), 129.8 (4C, C-ortho, C6H5CH2), 128.0 (4C,
C-meta, C6H5CH2), 126.8 (2C, C-para, C6H5CH2, C-5), 123.1 (C-6), 119.5 (C-8a),
115.8 (C-8), 64.5 (C-3), 45.2 (2C, C6H5CH2).
(6b) [8]: Colorless solid; mp: 180-181 °C. IR (KBr) ν; 3180, 3040, 2900, 1680, 1640,
1490, 1410, 1350, 1240, 1170, 1030, 810, 700, 620 cm-1. 1H NMR (200 MHz, CDCl3):
 9.48 (sb, 1H, H-1), 7.23 (d, J = 2.8, 1H, H-5), 7.11-6.99 (m, 10H, C6H5CH2), 6.87
(dd, J = 8.8, 2.8, 1H, H-7), 6.51 (d, J = 8.8, 1H, H-8), 3.75 (OMe-6), 3.53 (d, J = 12.8,
2H, C6H5CH2), 3.42 (d, J = 12.8, 2H, C6H5CH2). 13C NMR (50 MHz, CDCl3):  197.1
(C-4), 173.7 (C-2), 155.4 (C-6), 135.6 (2C, C-ipso, C6H5CH2), 134.6 (C-5a), 129.8
(4C, C-ortho, C6H5CH2), 128.0 (4C, C-meta, C6H5CH2), 126.8 (2C, C-para, C6H5CH2),
124.5 (C-7), 120.3 (C-8a), 117.3 (C-6), 107.9 (C-8), 64.1 (C-3), 55.5 (OMe-8), 45.2
(2C, C6H5CH2).

11
(6c): Yellowish solid; mp: 207-209 °C. IR (KBr) ν; 3320, 3040, 2920, 1690, 1650,
1590, 1480, 1350, 1270, 1190, 820, 750, 700 cm-1. 1H NMR (200 MHz, CDCl3): 
9.11 (sb, 1H, H-1), 7.89 (d, J = 2.4, 1H, H-5), 7.35 (dd, J = 8.6, 2.4, 1H, H-7), 7.08-
7.01 (m, 10H, C6H5CH2), 6.43 (d, J = 8.6, 1H, H-8), 3.49 (d, J = 12.8, 2H, C6H5CH2),
3.41 (d, J = 12.8, 2H, C6H5CH2). 13C NMR (50 MHz, CDCl3):  196.1 (C-4), 173.7 (C-
2), 139.1 (C-5a) 138.5 (C-7), 135.3 (2C, C-ipso, C6H5CH2), 129.7 (4C, C-ortho,
C6H5CH2), 129.4 (C-5), 128.2 (4C, C-meta, C6H5CH2), 127.0 (2C, C-para, C6H5CH2),
121.1 (C-6*), 117.5 (C-8), 115.9 (C-8a*), 64.7 (C-3), 45.3 (2C, C6H5CH2). HRMS
+
(ESI): m/z calcd. for C23H19BrNO2 [M+H]+: 420.0599; Found: 420.0592. Single
crystals suitable for X-ray diffraction were obtained after slow solvent evaporation
from an n-hexane/EtOAc solution [24].
(6d) [8]: Colorless solid; mp. 195-196 °C. IR (KBr) ν; 3200, 3060, 2920, 1690, 1650,
1600, 1500, 1380, 1260, 1070, 970, 700 cm-1. 1H NMR (200 MHz, CDCl3):  7.86 (sb,
1H, H-1), 7.35 (ddd, J = 7.6, 1.8, 0.5, 1H, H-5), 7.25-7.01 (m, 10H, C6H5CH2), 6.83-
6.77 (m, 2H, H-6, 7), 3.69 (s, 3H, OMe-8), 3.49 (d, J = 12.8, 2H, C6H5CH2), 3.42 (d, J
= 12.8, 2H, C6H5CH2). 13C NMR (50 MHz, CDCl3):  197.3 (C-4), 172.0 (C-2), 145.2
(C-8), 135.9 (2C, C-ipso, C6H5CH2), 130.6 (C-8a), 129.9 (4C, C-ortho, C6H5CH2),
128.0 (4C, C-meta, C6H5CH2), 126.8 (2C, C-para, C6H5CH2), 122.2 (C-6), 120.1 (C-
8a), 118.0 (C-5*), 115.8 (C-7*), 64.7 (C-3), 60.0 (OMe-8), 45.4 (2C, C6H5CH2).
(6e): Colorless solid; mp. 215-217 °C. IR (KBr) ν; 3230, 2920, 1690, 1650, 1590,
1490, 1380, 700 cm-1. 1H NMR (200 MHz, CDCl3):  8.10 (sb, 1H, H-1), 7.67 (d, J =
7.5, 1H, H-5), 7.13-7.02 (m, 11H, H-7, C6H5CH2), 6.84 (t, 1H, J = 7.6, H-6), 3.50 (d, J
= 12.8, 2H, C6H5CH2), 3.41 (d, J = 12.8, 2H, C6H5CH2), 2.02 (s, 3H, Me-8). 13C NMR

12
(50 MHz, CDCl3):  197.1 (C-4), 172.8 (C-2), 138.5 (C-8), 137.0 (C-7), 135.7 (2C, C-
ipso, C6H5CH2), 129.9 (4C, C-ortho, C6H5CH2), 127.9 (4C, C-meta, C6H5CH2), 126.9
(2C, C-para, C6H5CH2), 124.9 (C-6), 122.5 (C-5, C-5a), 120.0 (C-8a), 64.4 (C-3), 45.2
+
(2C, C6H5CH2), 16.2 (Me-8). HRMS (FAB) m/z: calcd. for C24H22NO2 [M+H]+:
356.1645; Found: 356.1654.
(7a) [6]: Colorless solid; mp. 163-164 °C. IR (KBr) ν; 3190, 3060, 2920, 1690, 1650,
1590, 1430, 1380, 1240, 1180, 980, 830, 750, 660 cm-1. 1H NMR (200 MHz, CDCl3):
 9.32 (sb, 1H, H-1), 7.88 (dd, J = 7.8, 1.5, 1H, H-5), 7.49 (ddd, J = 8.1, 7.4, 1.5, 1H,
H-7), 7.08 (ddd, J = 7.8, 7.4, 1.2, 1H, H-6), 6.94 (dd, J = 8.1, 1.2, 1H, H-8), 1.45 (s,
6H, Me-3). 13C NMR (50 MHz, CDCl3):  197.6 (C-4), 176.8 (C-2), 140.8 (C-5a),
135.9 (C-7), 127.9 (C-5), 123.5 (C-6), 118.5 (C-8a), 116.3 (C-8), 52.7 (C-3), 23.5 (2C,
Me-3).
(7b) [10c,d]: Almost colorless solid; mp. 175-176 °C. IR (KBr) ν; 3180, 3060, 2960,
1680, 1640, 1590, 1490, 1340, 1220, 1160, 1030, 820, 760, 650 cm-1. 1H NMR (200
MHz, CDCl3):  9.89 (sb, 1H, H-1), 7.38 (d, J = 1.5, 1H, H-5), 7.15 (dd, J = 7.7, 1.5,
1H, H-7), 7.00 (d, J = 8.1, 1H, H-8), 3.83 (s, 3H, OMe-6), 1.51 (s, 6H, Me-3). 13C
NMR (50 MHz, CDCl3):  197.8 (C-4), 176.3 (C-2), 155.8 (C-6), 134.9 (C-8a), 124.6
(C-7), 118.8 (C-4a), 117.7 (C-8), 109.0 (C-5), 55.7 (OMe-6), 52.4 (C-3), 23.6 (2C,
+
Me-3). HRMS (FAB) m/z: calcd. for C12H14NO3 [M+H]+: 220.0974; Found: 220.0974.
(7c) [28]: Pale brownish solid, mp. 215-217 °C. IR (KBr) ν; 3200, 3060, 2980, 1700,
1660, 1590, 1410, 1320, 1250, 1190, 840, 660 cm-1. 1H NMR (200 MHz, CDCl3): 
9.58 (sb, 1H, H-1), 8.05 (d, J = 2.0, 1H, H-5), 7.64 (dd, J = 8.5, 2.0, 1H, H-7), 6.93 (d,

13
J = 8.5, 1H, H-8), 1.51 (s, 6H, Me-3). 13C NMR (50 MHz, CDCl3):  196.3 (C-4), 176.1
(C-2), 139.6 (C-5a), 138.5 (C-7), 130.6 (C-5), 119.9 (C-6*), 117.9 (C-8*), 116.2 (C-
8a), 52.9 (C-3), 23.4 (2C, Me-3).
(7d): Colorless solid; mp. 158-159 °C. IR (KBr) ν; 3200, 3080, 2940, 1700, 1660,
1590, 1490, 1380, 1330, 1260, 1080, 990, 810, 730 cm-1. 1H NMR (200 MHz, CDCl3):
 8.03 (sb, 1H, H-1), 7.55-7.52 (m, 1H, H-5), 7.08-7.07 (m, 2H, H-6, 7), 3.94 (s, 3H,
OMe-8), 1.50 (s, 6H, Me-3). 13C NMR (50 MHz, CDCl3):  197.7 (C-4), 174.3 (C-2),
145.8 (C-8), 130.9 (C-8a), 122.7 (C-6), 119.0 (C-5), 118.6 (C-8a), 115.8 (C-7), 56.2
+
(OMe-8), 53.1 (C-3), 23.5 (2C, Me-3). HRMS (FAB) m/z: calcd. for C12H13NNaO3
[M+Na]+: 242.0793; Found: 242.0791.
(7e): Colorless solid; mp. 150-152 °C. IR (KBr) ν; 3200, 3080, 2920, 1680, 1640,
1590, 1450, 1380, 1220, 990, 800, 750, 670 cm-1. 1H NMR (200 MHz, CDCl3):  8.33
(sb, 1H, H-1), 7.81 (dd, J = 7.7, 1H, H-5), 7.40 (dd, J = 7.7, 1.5, 1H, H-7), 7.06 (t, J =
7.7, 1H, H-6), 2.36 (s, 3H, Me-8), 1.50 (s, 6H, Me-3). 13C NMR (50 MHz, CDCl3): 
197.8 (C-4), 175.5 (C-2), 138.9 (C-8), 137.1 (C-7), 126.0 (C-6*), 123.3 (C-5a), 122.9
(C-5*), 118.5 (C-8a), 52.7 (C-3), 23.4 (2C, Me-3), 16.7 (Me-8). HRMS (FAB) m/z:
+
calcd. for C12H14NO2 [M+H]+: 204.1019; Found: 204.1019.
(10a) [7a]: Colorless solid; mp. 80-82 °C. IR (KBr) ν; 3187, 3068, 3000, 2932, 1692,
1661, 1598, 1485, 1380, 1239, 1156, 926, 759, 666, 438 cm-1. 1H NMR (200 MHz,
CDCl3):  9.99 (sb, 1H, H-1), 7.87 (dd, J = 7.9, 1.4, 1H, H-5), 7.54 (ddd, J = 8.1, 6.9,
1.4, 1H, H-7), 7.06 (ddd, J = 7.9, 6.9, 1.0, 1H, H-6), 6.95 (d, J = 8.1, 1H, H-8), 5.63-
5.43 (m, 2H, CH2CH=CH2), 5.02-4.83 (m, 4H, CH2CH = CH2), 2.80-2.61 (m, 4H, -

14
CH2CH=CH2). 13C NMR (50 MHz, CDCl3):  196.8 (C-4), 174.8 (C-2), 141.2 (C-5a),
136.4 (C-7), 132.0 (2C, CH2CH=CH2), 127.6 (C-5), 123.7 (C-6), 119.8 (C-8a), 119.5
(2C, CH2CH=CH2), 116.2 (C-8), 61.6 (C-3), 42.9 (2C, CH2CH=CH2).
(10b): Colorless solid; mp. 159-161 °C. IR (KBr) ν; 3180, 3050, 2980, 1690, 1650,
1590, 1410, 1350, 1290, 1170, 1030, 910, 840, 700, 650 cm-1. 1H NMR (200 MHz,
CDCl3):  9.70 (sb, 1H, H-1), 7.37 (d, J = 2.8, 1H, H-5), 7.15 (dd, J = 8.8, 2.8, 1H, H-
7), 6.92 (d, J = 8.8, 1H, H-8), 5.65-5.51 (m, 2H, CH2CH=CH2), 5.07-4.91 (m, 4H,
CH2CH=CH2), 3.83 (s, 3H, OMe-6), 2.83-2.69 (m, 4H, CH2CH=CH2). 13C NMR (50
MHz, CDCl3):  196.7 (C-4), 173.9 (C-2), 155.8 (C-6), 135.1 (C-5a), 131.8 (2C,
CH2CH=CH2), 125.0 (C-7), 120.1 (C-8a), 119.3 (2C, CH2CH=CH2), 117.8 (C-8),
108.3 (C-5), 61.1 (C-3), 55.7 (OMe-6), 42.8 (2C, CH2CH=CH2). HRMS (ESI), m/z:
+
calcd. for C16H18NO3 [M+H]+: 272.1281; Found: 272.1293.
(10c): Yellowish solid; mp. 140-142 °C. IR (KBr) ν; 3180, 3060, 2960, 1690, 1650,
1590, 1410, 1380, 1280, 990, 920, 840, 650 cm-1. 1H NMR (200 MHz, CDCl3):  9.75
(sb, 1H, H-1), 8.04 (d, J = 2.3, 1H, H-5), 7.63 (dd, J = 8.5, 2.3, 1H, H-7), 6.89 (d, J =
8.5, 1H, H-8), 5.63-5.50 (m, 2H, CH2CH=CH2), 5.08-4.93 (m, 4H, CH2CH=CH2), 2.83-
2.69 (m, 4H, CH2CH=CH2). 13C NMR (50 MHz, CDCl3):  195.5 (C-4), 174.2 (C-2),
139.7 (C-5a), 138.8 (C-7), 131.4 (2C, CH2CH=CH2), 129.9 (C-5), 120.8 (C-6*), 119.7
(2C, CH2CH=CH2), 118.1 (C-8), 116.4 (C-8a*), 61.6 (C-3), 42.7 (2C, CH2CH=CH2).
+
HRMS (ESI), m/z: calcd. for C15H15BrNO2 [M+H]+: 320.0281; Found: 320.0283
(10d) [29]: Yellowish solid; mp. 83-85 °C. IR (KBr) ν; 3180, 3060, 2940, 1680, 1650,
1590, 1490, 1370, 1270, 920, 730 cm-1. 1H NMR (200 MHz, CDCl3):  8.34 (sb, 1H,

15
H-1), 7.56-7.47 (m, 1H, H-5), 7.10-7.01 (m, 2H, H-6, 7), 5.66-5.49 (m, 2H,
CH2CH=CH2), 5.11-4.91 (m, 4H, CH2CH=CH2), 3.93 (s, 3H, OMe-8), 2.83-2.65 (m,
4H, -CH2CH=CH2). 13C NMR (50 MHz, CDCl3):  197.2 (C-4), 172.6 (C-2), 146.2 (C-
8), 132.2 (2C, CH2CH=CH2), 131.6 (C-5a*), 123.1 (C-6), 120.2 (C-8a*), 119.7 (2C,
CH2CH=CH2), 118.8 (C-5), 116.4 (C-7), 62.1 (C-3), 56.6 (OMe-8), 43.0 (2C,
CH2CH=CH2).
(10e): Almost colorless solid; mp. 75-76 °C. IR (KBr) ν; 3240, 3080, 2920, 1690,
1640, 1590, 1470, 1370, 1220, 920, 780, 700 cm-1. 1H NMR (200 MHz, CDCl3): 
8.98 (sb, 1H, H-1), 7.84-7.79 (m, 1H, H-5), 7.42-7.38 (m, 2H, H-7), 7.01 (t, 2H, J =
7.7, H-6), 5.69-5.49 (m, 2H, CH2CH=CH2), 5.08-4.90 (m, 4H, CH2CH=CH2), 2.82-
2.63 (m, 4H, CH2CH=CH2), 2.37 (s, 3H, Me-8). 13C NMR (50 MHz, CDCl3):  196.7
(C-4), 173.5 (C-2), 139.2 (C-8), 137.4 (C-7*), 131.8 (2C, CH2CH=CH2), 125.3 (C-6*),
123.6 (C-5a#), 122.8 (C-5*), 119.6 (2C, CH2CH=CH2), 119.2 (C-8a#), 61.1 (C-3), 42.4
+
(2C, CH2CH=CH2), 16.8 (Me-3). HRMS (FAB), m/z: calcd. for C16H18NO2 [M+H]+:
256.1332; Found: 256.1327.
(11) [30]: Colorless solid; mp. 103-105 °C (Lit. 126-127 °C). IR (KBr) ν; 3200, 3060,
2920, 1690, 1650, 1590, 1440, 1390, 1290, 1160, 840, 750 cm-1. 1H NMR (200 MHz,
CDCl3):  10.2 (sb, 1H, H-1), 7.82 (dd, J = 7.8, 1.4, 1H, H-5), 7.44 (m, 1H, H-7), 7.03
(m, 1H, H-6), 6.95 (d, J = 8.0, 1H, H-8), 4.87-4.83 (m, 2H, CH2CH=CMe2), 1.51 (s,
3H, Z-CH2CH=CMe2), 1.43 (s, 3H, E-CH2CH=CMe2). 13C NMR (50 MHz, CDCl3): 
197.7 (C-4), 175.5 (C-2), 140.8 (C-5a), 135.8 (C-7*), 135.7 (2C, CH2CH=CMe2*),
125.9 (C-5), 123.1 (C-6), 119.6 (C-8a), 117.7 (2C, CH2CH=CMe2), 116.2 (C-8), 61.9
(C-3), 37.4 (2C, CH2CH=CMe2), 25.7 (2C, E-CH2CH=CMe2), 23.5 (2C, Z-
CH2CH=CMe2).

16
(12) [7a]: Colorless solid; mp. 101-102 °C. IR (KBr) ν; 3200, 2920, 1690, 1650, 1590,
1480, 1380, 750 cm-1. 1H NMR (200 MHz, CDCl3):  9.13 (sb, 1H, H-1), 7.95 (dd, J =
7.9, 1.6, 1H, H-5), 7.54 (ddd, J = 8.0, 7.3, 1.6, 1H, H-7), 7.08 (dd, J = 7.9, 7.3, 1H, H-
6), 6.94 (d, J = 8.0, 1H, H-8), 2.03-1.96 (m, 4H, CH2CH2Me), 1.26-1.23 (m, 4H,
CH2CH2Me), 0.83-0.79 (m, 6H, CH2CH2Me). 13C NMR (50 MHz, CDCl3):  198.1 (C-
4), 175.4 (C-2), 140.9 (C-5a), 135.6 (C-7), 127.3 (C-5), 123.4 (C-6), 119.8 (C-8a),
116.1 (C-8), 61.9 (C-3), 42.0 (2C, CH2CH2Me), 18.4 (2C, CH2CH2Me), 14.3 (2C,
CH2CH2Me).
Declaration of Competing Interest
The authors declare no competing financial interest.
Declaration of Competing Interest
No conflict of interest to declare.
Acknowledgments
This work was supported by CNPq (Processo 403471/2013-3), CONICET and
MINCyT (PICT 2014-0445). Dr. Ludger A. Wessjohann (Leibniz Institute of Plant
Biochemistry, Halle-Saale, Germany) is thanked for several HRMS determinations.
Dr. Teodoro S. Kaufman is acknowledged for fruitful discussions and revision of this
manuscript.

17
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23
Figure 1. a) Molecular structure of 6c. The displacement ellipsoids were drawn at
the 50% probability level and the hydrogen atoms were omitted for the sake of
clarity; b) unit cell of 6c.
Scheme 1. Alkylation of heterocyclic scaffolds 1-3 and products formation 4a-g.

24
Table 1. Optimization of the C,C-dialkylation of 5a to afford 6a and 7a.
EntryAlkylatingRX:5a
Base
(equiv.)
NaOH (2.0)
Time
(h)
24
Product
(Yield, %)
6a (43)
Solvent
Temp.
N°
1
agent ratio
BnBr
BnBr
BnBr
MeI
2:1
PhH/H2O (1:1)
PhH/H2O (1:1)
PhH/H2O (1:1)
PhH/H2O
reflux
reflux
reflux
reflux
reflux
2
3
4:1
NaOH (4.0)
K2CO3 (6.0)
KOH (6.0)
24
12
12
12
48
24
12
12
22
17
12
12
12
12
6a (68)
6a (85)
-
6:1
4
12:1
12:1
6:1
5
MeI
K2CO3 (6.0)
K2CO3 (6.0)
K2CO3 (6.0)
K2CO3 (6.0)
K2CO3 (6.0)
PhH/H2O
7a (17)
6a (40)
6
BnBr
BnBr
MeI
PhMe/H2O (1:1) reflux
a
7
6:1
MeCN
MeCN
Acetone
TFE
reflux
reflux
reflux
rt
-
8
12:1
12:1
7a (34)b
7a (11)
6a (78)
6a (97)
7a (17)
7a (14)
7a (18)
7a (52)
9
MeI
10
11
12
13
14
15
BnBr
BnBr
MeI
6:1 CF3CH2ONa (6.0)
6:1
K2CO3 (6.0)
K2CO3 (6.0)
KOH (6.0)
TFE
60 °C
reflux
reflux
reflux
rt
12:1
12:1
12:1
12:1
TFE
MeI
TFE
MeI
Ag2CO3 (6.0)
K2CO3 (Ag2O)
TFE
MeI
TFE
a 1,3,3-tris-benzylated quinolone (8) was mainly recovered.
b Compound 9 was the main product of this reaction.

25
Table 2. Scope of the C,C-dialkylation affording the 3,3-disubstituted quinoline-2,4-
diones.
Entry N°
RX
BnBr
BnBr
BnBr
BnBr
BnBr
MeI
R1
H
R2
H
Product N°
6a
Yield (%)
97
1
2
OMe
Br
H
H
6b
94
3
H
6c
81
4
OMe
Me
H
6d
92
5
H
6e
97
6
H
7a
52a
31a
17a
40a
37a
61
7
MeI
OMe
Br
H
H
7b
8
MeI
H
7c
9
MeI
OMe
Me
H
7d
10
11
12
13
14
15
16
17
MeI
H
7e
AllylBr
AllylBr
AllylBr
AllylBr
AllylBr
PrenylBr
n-PrI
H
10a
10b
10c
10d
10e
11
OMe
Br
H
H
60
H
54
OMe
Me
H
56
H
62
H
47
H
H
12
8a
aThe reaction was performed in the presence of Ag2O.