Novel quinoline-imidazolium adducts via the reaction of 2-oxoquinoline-3-carbaldehyde and quinoline-3-carbaldehydes with 1-butyl-3-methylimidazolium chloride [BMIM][Cl]

Article abstract of DOI:10.1016/j.tetlet.2014.05.094

A library of hydroxyquinolin-3-ylmethylimidazolium adducts were prepared in high yields from the reaction of [BMIM][Cl] with various substituted quinoline-3-carbaldehydes and 2-oxoquinoline-3-carbaldehydes under mild conditions by using sodium acetate in MeCN under ultrasound irradiation. The use of sodium acetate and imidazolium chloride was crucial for the success of these CC bond forming reactions. Attempted coupling with thiazolium bromide led instead to quinoline-3-carboxylic acid.

Full text of DOI:10.1016/j.tetlet.2014.05.094

Accepted Manuscript
Novel Quinoline-Imidazolium Adducts via the Reaction of 2-Oxoquinoline-3-
Carbaldehyde and Quinoline-3-Carbaldehydes with 1-Butyl-3-Methylimidazo-
lium Chloride [BMIM][Cl]
Kenneth K. Laali, Daniel Insuasty, Rodrigo Abonia, Braulio Insuasty, Scott D.
Bunge
PII:
S0040-4039(14)00925-3
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.05.094
TETL 44685
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
14 May 2014
22 May 2014
24 May 2014
Please cite this article as: Laali, K.K., Insuasty, D., Abonia, R., Insuasty, B., Bunge, S.D., Novel Quinoline-
Imidazolium Adducts via the Reaction of 2-Oxoquinoline-3-Carbaldehyde and Quinoline-3-Carbaldehydes with 1-
Butyl-3-Methylimidazolium Chloride [BMIM][Cl], Tetrahedron Letters (2014), doi: http://dx.doi.org/10.1016/
j.tetlet.2014.05.094
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1
Novel Quinoline-Imidazolium Adducts via the Reaction of 2-Oxoquinoline-3-
Carbaldehyde and Quinoline-3-Carbaldehydes with 1-Butyl-3-Methylimidazolium
Chloride [BMIM][Cl]
Kenneth K. Laali*[a], Daniel Insuasty [a,b], Rodrigo Abonia*[b], Braulio Insuasty[b], and Scott D. Bunge[c]
[a] Department of Chemistry, University of North Florida, 1 UNF Drive, Jacksonville, Florida 32224,
[c]
USA; [b] Department of Chemistry, Universidad del Valle, A.A. 25360, Cali-Colombia; Department
of Chemistry and Biochemistry, Kent State University, Kent, OH 44242, USA
Abstract: A library of hydroxyquinolin-3-ylmethylimidazolium adducts were prepared in high yields
from the reaction of [BMIM][Cl] with various substituted quinoline-3-carbaldehydes and 2-
oxoquinoline-3-carbaldehydes under mild conditions by using sodium acetate in MeCN under
ultrasound irradiation. The use of sodium acetate and imidazolium chloride was crucial for the success
of these C-C bond forming reactions. Attempted coupling with thiazolium bromide led instead to
quinoline-3-carboxylic acid.
Keywords: quinolone-3-carbaldehyde; ionic liquids (IL´s); 3-butyl-1-methylimidazolium acetate; N-
heterocyclic carbenes (NHCs), hydroxyquinolin-3-ylmethylimidazolium adducts; thiazolium salts;
quinoline-3-carboxylic acids.
*Corresponding Author: Tel: 904-620-1503, Fax: 904-620-3535. E-mail: kenneth.laali@UNF.edu
(Kenneth K. Laali)

2
Quinolines and their oxo-derivatives have attracted considerable interest for many years due to
their presence in the skeleton of a large number of bioactive compounds and natural products.1 Among
them, 2-chloro- and 2-oxoquinoline-based compounds have recently emerged as promising antibiotic,
CNS stimulant and effective lead structures for the tyrosine kinase receptors (KDR) inhibition
mechanism, a key class of enzymes for the tumor cell proliferation.2 Thus, the 2-chloro derivatives 1
and 2 have displayed antimicrobial activity,2a,2b compounds 3 and 4 have been evaluated as potent and
selective cannabinoid-2 receptor ligands through a bioisosteric approach,2c while structures 5 represent
some examples of the 2-oxoquinoline based anti-tumor agents2d as well as a series of
benzimidazoloquinolin-2-ones 6 recently reported by one us2e,2f (Figure 1).
R
O
N
N
HN
Cl
O
N
N
R1
HO
R
R1
N
S
O
O
N
Cl
2
1
O
Ad
O
N
H
Ad
N
H
N
O
N
O
3
4
Ad = 1-Adamantyl
R1
R
N
O
N
O
Y
N
N
R
N
H
N
H
R1
H
6
5
Figure 1. The 2-chloro- and 2-oxoquinoline based compounds of biological interest
Imidazolium salts, especially those that are room temperature ionic liquids (RTILs) are
among the most widely investigated classes of onium salts with wide application as alternative
solvents and catalysts.3 Due to surprisingly high acidity at the C2 position imidazolium and

3
thiazolium salts are easily deprotonated,4a,4b and their conjugate base acts as source of N-
heterocyclic carbenes (NHCs) that are increasing employed as organocatalyst in synthesis.4c-g
In connection to an ongoing program on the development of quinoline-based structures of
biological interest,2e,f-5 and our continuing interest in synthesis and catalysis in ILs,6 herein we
report a facile one-pot synthetic method for the preparation of novel hydroxyquinolin-3-
ylmethylimidazolium adducts by reacting substituted quinoline-3-carbaldehydes and the 3-butyl-1-
methylimidazolium chloride.
In an attempt to develop an alternative procedure to obtain the biologically active bis-
quinolone based chalcone 7a5 by using a basic ionic liquid (IL) acting both as solvent and as
catalyst, a mixture of the N-butylformylquinolone 17a (2 equiv), acetone (1 equiv) and the IL
o
[BMIM][OAc] (3 mL) was subjected to reaction under ultrasound irradiation at 80 C. Upon
consumption of 17a (TLC control) a white solid was formed, isolated and purified. A complete
spectroscopic analysis indicated that the structure of this solid corresponded to the
hydroxyquinolin-3-ylmethylimidazolium adduct 8a and not to the expected bis-chalcone 7a
(Scheme 1). In order to improve the synthesis of the unexpected adduct 8a the reaction was
repeated between the formylquinolone 17a (1 equiv), 3-butyl-1-methylimidazolium chloride
[BMIM][Cl] (1.3 equiv) and AcONa (1.0 equiv) in acetonitrile (3 mL) as solvent, under
o
microwave irradiation at 80 C, ([BMIM][OAc] is formed in situ by reacting [BMIM][Cl] with
AcONa). After purification of the crude reaction mixture compound 8a was isolated in 89% yield.7
Scheme 1. Synthesis of the quinoline-imidazolium adduct 8a by addition of the [BMIM]Cl to the
formylquinolone 17a

4
In order to expand the scope and to evaluate the generality of our above optimized protocol
we performed the synthesis of diversely substituted N-butyl- and N-benzyl-quinolones 17 and 19,
respectively, as well as the O-butyl- and O-benzyl-quinolines 18 and 20 (see supplementary
information), with the aim to obtain a new series of quinolone-based imidazolium adducts type 8a
and analogues.
At the onset, a series of 2-chloroquinoline-carbaldehydes 15 and formyl-quinolones 16 were
prepared according to Scheme 2.
O
O
Ac2O
DMF
H
R
R
R
N
NH2
13a-e
POCl3
HCl, K2CO3
N
Cl
H
15a-e
14a-e
AcOH
R: a = H, b = 4-Me, c = 4-MeO
d = 3-Cl, e = 2-Me
Reflux
O
O
H
R
N
H
16a-e
Scheme 2. General procedure for the synthesis of the starting formyl-quinolones 15 and 168,9
Then, alkylation and benzylation of 16a-e under mild reaction conditions furnished the key
N- and O-butyl and N- and O-benzyl quinolines 17, 18, 19 and 20 (Scheme 3). In all cases the
mixtures of both N- and O- isomers were easily separated by column chromatography.
Scheme 3. General procedure for the synthesis of the key N- and O-butyl, and N- and O-benzyl
quinolines 17, 18, 19 and 20

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Reaction of these compounds with [BMIM][Cl] under the established conditions led to the
formation of adducts 8-12 in acceptable to good yields (Scheme 4).
Scheme 4. Synthesis of the novel hydroxyquinolin-3-ylmethylimidazolium adducts 8-12
Compounds 8-12 were fully characterized by NMR (1H and 13C) and Electrospray MS
techniques. Compounds 8a, 10a, 11c and 12a produced suitable crystals for X-ray analysis,10
unambiguously confirming the proposed structures for 8-12. The thermal ellipsoid plots for 10a
and 11c are shown in Figure 2. In the solid-state, for 10a and 11c planes generated from the
imidazolium and quinoline rings bisect each other with dihedral angles (88.16o and 86.72o
respectively). This orientation is likely to reduce steric repulsion with the methyl and butyl
substituents of the imidazolium ring. The unit cells clearly show the presence of one water
molecule along with one chloride ion per molecule.
Figure 2. Thermal ellipsoid plots of 10a and 11c with 50% probability ellipsoids. Hydrogen
atoms, chloride anions, and water molecules have been omitted for clarity.

6
Formation of hydroxyquinolin-3-ylmethylimidazolium adducts 8-12 reflect the in situ formation
of NHC-carbenes under mild conditions and their subsequent coupling with the quinolone- and
quinoline-aldehydes 15-19.11
A number of attempts were made to couple 17 with other imidazoliums, employing AcONa,
Et3N, or MeONa/MeOH as base but none of these conditions led to the formation of adducts 21 or
22 (Scheme 5). Therefore the use of sodium acetate and [BMIM][Cl] appear crucial for the success
of these C-C bond forming reactions.
ACN (2 mL)
AcONa (1 equiv)
))), 80 °C
-
O2N
EtSO4
ACN (2 mL)
N
N
AcONa (2 equiv)
))), 80 °C
O
O
O2N
OH
H
R
R
+
N
N
N
O
N
-
ACN (2 mL)
EtSO4
Et3N
))), 80 °C
21
17
MeOH
MeONa
OTf
N
N
Tf
Tf
OH
O
O
ACN (2 mL)
H
+
N
N
Tf
Tf
R
R
AcONa (1 equiv)
N
O
N
OTf
22
17
Scheme 5. Attempted coupling with other imidazoliums under various conditions
In an effort to extend this chemistry to other azolium salts, formyl-quinolone 17a and 3-
butyl-4-methylthiazolium chloride were allowed to react under similar reaction conditions.
Contrary to expectation, the quinolone carboxylic acid 23a was obtained instead of the thiazolium
type adduct 8a (Scheme 6). The same behavior was observed when aldehydes 15a and 18e were
tried, affording the corresponding carboxylic acids 24a and 24e. Structure 24e was unambiguously
confirmed by X-ray analysis (see Supplementary Information).

7
Scheme 6. Synthesis of quinolone carboxylic acids 23-24 mediated by the thiazolium salt.
Formation of the imidazolium adducts 8-12 as well as the quinolone-based carboxylic acids
23-24 should be supported by the formation of a common zwitterionic species 26 generated by the
addition of the corresponding imidazolium (R2 = H, A = NMe) or thiazolium (R2 = Me, A = S)
carbenes 2512 to the aldehydes 17a and their analogues (Scheme 7). In the case of imidazolium
derivatives rapid protonation of species 26 would lead to the isolated adduct 8a and its analogues.
For the thiazolium derivatives, formation of a highly reactive Breslow type intermediate 28 and its
subsequent oxidation mediated by molecular oxygen13 could account for the formation of the
carboxylic acid 23a and its analogues. In this sense, the selective formation of the Breslow
intermediate 28 for the thiazolium derivatives may be associated with the ability of sulfur to expand
its valence shell thus activating the proton migration process in the CHO- functionality of 26 via the
key species 27a. When “A” = NMe in 26, the stabilized species 27a is not produced and a rapid
protonation of the CHO- functionality leads to the isolated hydroxyl derivative 8a. Alternatively, an
H-bonded species 27b may form and act as precursor to 28.

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Scheme 7. Suggested mechanistic pathways for the formation of the imidazolium adduct 8a, the
carboxylic acid 23a, and their related structures.
In summary we have discovered a facile one-pot approach for the preparation of a library of
hydroxyquinolin-3-ylmethylimidazolium adducts in high yields by reacting various substituted
quinoline-3-carbaldehydes and 2-oxoquinoline-3-carbaldehydes with [BMIM][Cl] under mild
conditions by using sodium acetate/MeCN under ultrasound irradiation. Attempted extension of
this methodology to thiazolium adducts led instead to quinoline-3-carboxylic acids.
Supplementary Information (see footnote on the first page of this article): Complete
experimental procedures and characterization data for the products 8-12 and 23-24 are given.
CCDC 1001927-1001931 contain the supplementary crystallographic data for this paper. These

9
data can be obtained free of charge from the Cambridge Crystallographic Data Center via
ccdc.cam.ac.uk/data_request/cif.
Acknowledgements: RA and BI thank Universidad del Valle for financial support. DI thanks
COLIENCIAS for a doctoral fellowship and for the opportunity to spend 6 months in KL’s lab at
University of North Florida as a visiting graduate student. KL thanks UNF for the award of
Presidential Professorship.
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To a solution of the respective quinolones (16d,e; 17a-d and 19a) or the quinolines
15a,d,e and 18b-e (1 equiv) in acetonitrile (3 mL), 3-butyl-1-methylimidazolium chloride
(1.3 equiv) and AcONa (1.0 equiv) were added. The mixture was subjected to ultrasound
o
irradiation at 80 C during 1-7h. The completion of the reaction was monitored by TLC.
After solvent was removed under reduced pressure, the resulting solid was dissolved in
H2O and extracted with CH2Cl2 (3 x 2 mL). The combined organic layers were dried with
MgSO4 and the solvent was removed under reduced pressure. The residue was washed
with hexanes to afford products 8-12. Representative data for 8a: White solid. 89% yield,
1
mp, 110-111 °C, IR (cm-1, CH2Cl2): ν 3410 (OH), 1589 (C=C), 1651 (C=O); H NMR
(500 MHz, CDCl3) δ 8.43 (s,1H), 7.74 (dd, J = 7.8, 1.5 Hz, 1H), 7.63 (t, J = 8.7 Hz, 1Hz),

11
7.39 (d, J = 8.6 Hz, 1H), 7.33 (t, J = 7.9 Hz, 1H), 7.09 (d, J = 2.0 Hz, 1H), 7.02 (d, J = 2.0
Hz, 1H), 6.36 (d, J = 1.8 Hz, 1H), 4.24 (s, 3H), 4.23 – 4.08 (m, 4H), 1.76 – 1.59 (m, 3H),
1.45 – 1.39 (m, 3H), 1.20 – 1.12 (m, 2H), 0.97 (t, J = 7.4 Hz, 3H), 0.71 (t, J = 7.4 Hz,
3H); 13C NMR (126 MHz, CDCl3) δ 160.3, 146.7, 138.4, 136.7, 136.7, 136.4, 131.2,
129.8, 128.7, 122.8, 120.3, 114.2, 61.0, 48.1, 42.2, 36.8, 31.8, 29.5, 20.5, 19.5, 13.8, 13.3.
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