Straightforward synthesis of 2-propylquinolines under multicomponent conditions in fluorinated alcohols

Article abstract of DOI:10.1016/j.jfluchem.2012.12.006

The synthesis of 2-propylquinolines, a family of antileishmanial agents, is reported. Among the pathways explored, the 3-component Povarov reaction between butyraldehyde, aromatic amines and ethyl vinyl ether in trifluoroethanol (TFE), followed by an oxidation, offers a convenient entry to 2-propylquinolines with various substituents on positions 5-8.

Full text of DOI:10.1016/j.jfluchem.2012.12.006

Journal of Fluorine Chemistry 152 (2013) 94–98
Contents lists available at SciVerse ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Straightforward synthesis of 2-propylquinolines under multicomponent
conditions in fluorinated alcohols
*
**
`
Ch. Venkateswarlu, P.V. Balaji, Kavita De, Benoit Crousse, Bruno Figadere , Julien Legros
ˆ
Faculte´ de Pharmacie, BioCIS UMR 8076, Univ Paris Sud and CNRS, 5 rue J.-B. Cle´ment, F-92296 Chatenay-Malabry, France
A R T I C L E I N F O
A B S T R A C T
Article history:
The synthesis of 2-propylquinolines, a family of antileishmanial agents, is reported. Among the pathways
explored, the 3-component Povarov reaction between butyraldehyde, aromatic amines and ethyl vinyl
ether in trifluoroethanol (TFE), followed by an oxidation, offers a convenient entry to 2-propylquinolines
with various substituents on positions 5–8.
Received 15 November 2012
Received in revised form 13 December 2012
Accepted 14 December 2012
Available online 29 December 2012
ß 2012 Elsevier B.V. All rights reserved.
Keywords:
Domino reaction
Michael addition
HFIP
Aniline
Heterocycles
1. Introduction
these lines we now describe the synthesis of novel 2-substituted
quinolines bearing various substituents on positions 5–8.
Quinolines represent an important class of heterocycles with
applications as ligands for catalysis and as active ingredients in
pharmacy [1]. However, their activity is closely related to the nature
and position of the substituents on the ring. Notably, 2-substituted
quinolines exhibit antitrypanosomal [2,3], antiretroviral [4], anti-
plasmodial [5], nematocidal and trichomonacidal activities [6].
Among them, the chimanines, which are structurally simple
naturally occurring quinolines isolated from Galipea longiflora trees
[7], have shown significant activity against several leishmania
strains, and in vivo tests have demonstrated their oral leismanicide
property [8–10]. Moreover, pharmacomodulation revealed that
quinolines bearing a n-propyl chain in position 2 were promising
candidates [9]. To date, few methods have been reported for the
synthesisofsuch2-propylquinolines[11,12]. Inspiredbytheworkof
Webb [13], one of us reported that reacting the quinolinium salt 2a
with n-propyl magnesium bromide afforded the target 2-propyl-
quinoline 3a in 67% yield (Scheme 1) [14].
2. Results and discussion
The fluorinated alcohols trifluoroethanol (TFE) and hexafluor-
oisopropanol (HFIP) exhibit a booster effect as reaction medium,
and they thus promote various reactions by pure solvent effect
[15–24]. For example, we recently reported that electron-rich
aromatic amines and methyl vinyl ketone (MVK) reacted in
refluxing HFIP under air atmosphere to yield quinolines with a
methyl substituent in position 4 [25]. This synthesis went through
a domino aza-Michael addition/cyclization/dehydration/oxidation
sequence. In this context, our work was oriented toward the
preparation of novel quinolines with substituents in position 5–8
by reacting substituted aromatic amines with acrolein in HFIP,
furnishing thus precursors of novel 2-propylquinolines (Scheme 2,
path a).
First assessments were performed with 2,3-dimethoxyaniline
in refluxing HFIP, as previously described with methyl vinyl
ketone: no reaction took place between the aromatic amine and
the Michael acceptor, but the full polymerization of acrolein
occurred. Unfortunately, polymerization process was so fast in
HFIP that even decreasing the temperature to 0 8C did not avoid
this competitive path to take place. Best results were attained by
slowly adding a solution of acrolein in dichloromethane to a
solution of dimethoxyaniline in HFIP at 0 8C: low conversion of the
aniline into 6,7-dimethoxyquinoline 1b was obtained (25% yield,
However, due to the limited availability of the starting
materials this path has not been intensively developed. Along
* Corresponding author.
** Corresponding author at: Normandie Univ, COBRA UMR 6014, Univ Rouen, INSA
Rouen and CNRS, 1 rue Tesnie`re, 76821 Mont-Saint-Aignan, France.
E-mail addresses: bruno.figadere@u-psud.fr (B. Figade`re),
julien.legros@univ-rouen.fr (J. Legros).
0022-1139/$ – see front matter ß 2012 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.jfluchem.2012.12.006

C. Venkateswarlu et al. / Journal of Fluorine Chemistry 152 (2013) 94–98
95
Scheme 1. Synthesis of 2-propylquinoline [14].
Scheme 3. Synthesis of 6,7-dimethoxyquinoline (1b) through Michael addition.
a convenient access to tetrahydroquinolines [26,27]. Advanta-
geously, this reaction can be performed in a 3-component fashion
(3-CR) by directly mixing aldehyde (even enolizable), aryl amine
and enol ether in TFE as solvent [28,29]. Recently, we reported an
extension of this method for the synthesis of 2-substituted 8-
aminoquinolines as 2,9-disubstituted phenanthroline precursors
[30]. These aminoquinolines were obtained by using our 3-CR
Scheme 2. Strategies for the synthesis of novel 2-propylquinolines.
approach, followed by a one-pot
b-elimination/oxidation se-
Scheme 3). Several other attempts (higher amounts of acceptor,
lower temperature, reaction in darkness) did not lead to any
significant improvement on the reaction outcome. Unfortunately,
assessing less reactive amines (aniline, 4-chloroaniline, 4-nitroani-
line, . . .) did not afford any conversion of the nucleophile that
remained unchanged in the medium.
Due to these disappointing results, which did not furnish
enough materials to make this pathway viable for the synthesis of
2-propylquinolines, it was decided to switch to another strategy.
The Povarov reaction between aryl imines and enol ethers provides
quence. Hence, we reasoned that this strategy could be applied to
the synthesis of 2-propylquinolines starting from butyraldehyde
(Scheme 2, path b). Thus, butyraldehyde was reacted with a variety
of substituted anilines and ethyl vinyl ether (EVE) in TFE to afford
the corresponding tetrahydroquinolines. It is worth noting that, as
previously reported, the Povarov reaction did not occur in other
solvents (CH2Cl2, MeCN, EtOH) than TFE or HFIP [15,31].
After evaporation of the solvent, the obtained compounds were
immediately oxidized into quinolines by mean of aq. HCl 6N under
O2 atmosphere (Table 1).
Table 1
One pot synthesis of 2-propylquinolines from anilines through Povarov reaction.a
1. butyraldehyde, EVE
TFE, rt, 2 h
R
R
2. aq. HCl, O2 atm.
rt, 16 h
N
NH2
Entry
1
Product
Yield (%)
3a
3b
51
N
2
38
MeO
MeO
O
N
3
4
3c
39
37
O
N
3d
OMe
OMe
N
N
5
3e
55

96
C. Venkateswarlu et al. / Journal of Fluorine Chemistry 152 (2013) 94–98
Table 1 (Continued )
Entry
6
Product
Yield (%)
54
3f
N
7
3g
61
N
N
OH
8
9
3h
3i
52
34
SMe
Cl
N
N
OH
Cl
10
3j
40
OMe
11
12
3k
3l
41
43
Cl
N
CF3
N
13
3m
42
N
CF3
a
Conditions: (1) aryl amine, butyraldehyde (1.5 eq.), EVE (3 eq.) in TFE at r.t. for 2 h, then (2) aq. HCl 6 N (3 eq.), O2 atm. in MeCN at r.t. for 16 h.
The reaction with simple aniline proceeded well and afforded
the propylquinoline 3a in a good 51% yield (entry 1). Yields in
products were lower when starting from aryl amines bearing
alkoxy electron donating groups, whatever the positions of the
substituents were (quinolines 3b–d: 37–39%; Entries 2–4). In
contrast, the presence of alkyl chains (2-isopropoxy- or 2,5-
dimethylaniline) gave better yields in quinolines 3e and 3f (55%
and 54% yields, respectively; entries 5 and 6) as well as hydroxy
and thioether moieties (starting from 2-hydroxy-5-methyl- and
2-(methylthio)aniline): 61% and 52% yields in 3g and 3h,
respectively (entries 7 and 8). Chlorinated quinolines 3i–k were
obtained from 5-chloro-5-hydroxy-, 5-chloro-5-methoxy- and
4-chloroanilines in 34–41% yields (entries 9–11). Finally,
this process allowed the synthesis of CF3-containing quinolines
3l and 3m in 43% and 42% yields respectively (entries 12
and 13).
3. Conclusions
In summary, two pathways have been explored to prepare new
2-propylquinolines, a family of antileishmanial compounds. In a
first instance, the reaction between electron-rich anilines and
acrolein afforded quinolines in poor yields. Conversely, we have
been able to prepare a set of 2-propylquinolines from inexpensive
chemicals (anilines, butyraldehyde and ethyl vinyl ether) in a one-
pot sequence. Among these molecules, ten of them are new and
should be further biologically assessed against leishmania strains.
4. Experimental
4.1. Synthesis of quinoline 1b
To a solution of the aromatic amine (1.5 mmol) in HFIP (1.5 mL)
at 0 8C, a solution of acrolein (4.5 mmol) in dichloromethane
(4.5 mL) was added dropwise. The reaction was stirred at 0 8C for
1 h after which the solvent was evaporated under vacuum and the
product was purified by column chromatography on silica gel
(cyclohexane/AcOEt 50:50).
Thus, by performing two consecutive tandem processes (first
imine formation/Povarov reaction then
b-elimination/oxidation),
a straightforward synthesis of several 2-propylquinolines bearing
substituents on positions 5–8, including 10 new molecules, has
been performed (37–61% yields overall).

C. Venkateswarlu et al. / Journal of Fluorine Chemistry 152 (2013) 94–98
97
6,7-Dimethoxyquinoline (1b) [32]. Orange oil (71 mg, 25% yield).
1H NMR (300 MHz, CDCl3):
= 3.91 (s, 3H), 3.94 (s, 3H), 6.93 (s, 1H),
7.15 (dd, J = 4.5, 8.3 Hz, 1H), 7.33 (s, 1H), 7.88 (dd, J = 1.5, 8.2 Hz,
1H), 8.62 (dd, J = 1.6, 4.5 Hz, 1H). 13C NMR (75 MHz, CDCl3):
d = 14.0, 17.9, 18.5, 22.8, 41.1, 120.6, 125.7, 125.8, 128.9, 131.9,
d
132.5, 134.7, 147.2, 160.9. HRMS m/z = calcd. for C14H18N [M+H+]:
200.1439; found: 200.1444.
5-Methyl-2-propylquinolin-8-ol (3g). Dark yellow liquid
(610 mg, 61%). 1H NMR (300 MHz, CDCl3):
d = 1.02 (t, J = 7.5 Hz,
3H), 1.87 (sex, J = 7.8 Hz, 2H), 2.56 (s, 3H), 2.95 (t, J = 7.5 Hz, 2H),
7.03 (d, J = 9 Hz, 1H), 7.17 (t, J = 7.7 Hz, 1H), 7.33 (d, J = 7.7 Hz, 1H),
8.17 (d, J = 9 Hz, 1H). 13C NMR (75 MHz, CDCl3):
d = 13.9, 17.8, 22.7,
d
= 56.0, 105.1, 107.9, 119.4, 123.8, 134.1, 145.3, 148.0, 149.7,
152.4. ESI m/z (rel int): 190 [M+H]+ (100).
4.2. General procedure for the synthesis of 2-propylquinolines 3a–m
40.4, 109.0, 121.8, 124.1, 126.5, 133.1, 135.9, 137.9, 150.1, 160.0.
Anal. Calcd. for C13H15NO: C, 77.58; H, 7.51; N, 6.96. Found: C,
77.17; H, 7.88; N, 6.42.
To a stirred solution of aryl amine (5 mmol) and n-butyralde-
hyde (7.5 mmol, 541 mg) in trifluoroethanol (5 mL), ethyl vinyl
ether (15 mmol, 1.08 g) was added and the mixture was stirred for
2 h at 20 8C. Then the reaction mixture was concentrated to
dryness under reduced pressure and then diluted with acetonitrile
(5 mL). The mixture was cooled to 0 8C and then aqueous HCl 6 N
(15 mmol, 2.5 mL) was added. The reaction mixture was allowed to
attain room temperature and stirred under oxygen atmosphere
(1 atm.). After 16 h, the medium was neutralized with a saturated
aqueous solution of NaHCO3 and then extracted with dichlor-
omethane (3 Â 30 mL). Combined organic layer were washed brine
solution (40 mL) and dried over anhydrous MgSO4. The crude
product was concentrated under vacuum and purified by column
chromatography over silica gel (60–120 mesh; cyclohexane/ethyl
acetate 75:25).
8-(Methylthio)-2-propylquinoline (3h). Yellow liquid (566 mg,
52%). 1H NMR (300 MHz, CDCl3):
d = 7.93 (d, J = 8.4 Hz, 1H), 7.43
(dd, J = 7.8, 0.9 Hz, 1H), 7.34 (t, J = 7.5 Hz, 1H), 7.28–7.18 (m, 2H),
2.93–2.88 (m, 2H), 1.82 (sext, J = 7.5 Hz, 2H), 0.96 (t, J = 7.5 Hz, 3H).
13C NMR (75 MHz, CDCl3):
d = 161.8, 144.9, 139.3, 136.1, 126.3,
125.6, 123.2, 122.4, 122.0, 40.9, 22.7, 14.2, 14.0. HRMS m/z = calcd.
for C13H15NNaS [M+Na+]: 240.0823; found: 240.0825.
5-Chloro-2-propylquinolin-8-ol (3i). Dark yellow liquid (380 mg,
34%). 1H NMR (300 MHz, CDCl3):
d = 8.39 (d, J = 8.4 Hz, 1H), 7.45–
7.39 (m, 2H), 7.06 (d, J = 8.1 Hz, 1H), 2.98–2.91 (m, 2H), 1.93–1.80
(sext, J = 7.5 Hz, 2H), 1.01 (t, J = 7.5 Hz, 3H). 13C NMR (75 MHz,
CDCl3):
d = 161.3, 150.9, 138.0, 133.3, 126.3, 124.6, 123.0, 120.2,
109.7, 40.3, 22.5, 13.9. HRMS m/z = calcd. for C12H13ClNO [M+H+]:
222.0686; found: 222.0687.
2-Propylquinoline (3a) [14]. Pale yellow oil (436 mg, 51% yield).
1H NMR (300 MHz, CDCl3):
d
= 1.02 (t, J = 7.5 Hz, 3H), 1.85 (sex,
5-Chloro-8-methoxy-2-propylquinoline (3j). Yellow solid
(469 mg, 40%). mp: 68 8C. 1H NMR (300 MHz, CDCl3):
d = 8.41 (d,
J = 8.7 Hz, 1H), 7.43 (d, J = 8.7 Hz, 1H), 7.42 (d, J = 8.7 Hz, 1H), 6.92
(d, J = 8.4 Hz, 1H), 4.04 (s, 3H), 3.05–2.99 (m, 2H), 1.84 (sext,
J = 7.2 Hz, 2H), 1.01 (t, J = 7.2 Hz, 3H). 13C NMR (75 MHz, CDCl3):
J = 7.2 Hz, 2H), 2.95 (t, J = 7.5 Hz, 2H), 7.29 (d, J = 7.5 Hz, 1H), 7.47 (t,
J = 6 Hz, 1H), 7.67 (t, J = 6 Hz, 1H), 7.76 (d, J = 9 Hz, 1H), 8.06 (d,
J = 9 Hz, 2H). 13C NMR (75 MHz, CDCl3):
d = 14.0, 23.3, 41.3, 121.4,
125.6, 126.7, 127.5, 128.8, 129.3, 136.2, 147.9, 162.9.
6,7-Dimethoxy-2-propylquinoline (3b). Dark yellow liquid
d = 162.4, 154.1, 140.1, 132.9, 125.2, 122.4, 122.0, 107.4, 56.0, 41.1,
(426 mg, 38%). 1H NMR (300 MHz, CDCl3):
d
= 7.81 (d, J = 8.4 Hz,
23.2, 14.0. HRMS m/z: calcd. for C13H14ClNNaO [M+Na+]: 258.0662;
found: 258.0663.
1H), 7.31 (s, 1H), 7.06 (d, J = 8.4 Hz, 1H), 6.92 (s, 1H), 3.93 (s, 3H),
3.90 (s, 3H), 2.83–2.78 (m, 2H), 1.74 (sext, J = 7.5 Hz, 2H), 0.93 (t,
6-Chloro-2-propylquinoline (3k). Pale yellow oil (421 mg, 41%
yield). 1H NMR (300 MHz, CDCl3):
d = 1.01 (t, J = 7.5 Hz, 3H), 1.83
J = 7.5 Hz, 3H). 13C NMR (75 MHz, CDCl3):
d
= 160.6, 152.3, 149.2,
144.9, 134.6, 122.0, 119.6, 107.8, 105.2, 56.2, 56.0, 41.2, 23.6, 14.1.
HRMS m/z = calcd. for C14H18NO2 [M+H+]: 232.1338; found:
232.1347.
(sex, J = 7.8 Hz 2H), 2.93 (t, J = 7.5 Hz, 2H), 7.30 (d, J = 9 Hz, 1H),
7.60 (dd, J = 9, 3 Hz, 1H), 7.73 (d, J = 3 Hz, 1H), 7.96 (d, J = 9 Hz, 2H).
13C NMR (75 MHz, CDCl3):
d = 14.0, 23.1, 41.2, 122.3, 126.1, 127.3,
6-Propyl-[1,3]dioxolo[4,5-g]quinoline (3c). Gray solid (415 mg,
130.1, 130.5, 131.2, 135.2, 146.3, 163.2. Anal. Calcd. for C12H12ClN:
C, 70.07; H, 5.88; Cl, 17.24; N, 6.81. Found: C, 70,44; H, 5.65; Cl,
17,26; N, 6,74.
39%). mp: 110 8C. 1H NMR (300 MHz, CDCl3):
d = 7.86 (d, J = 8.4 Hz,
1H), 7.34 (s, 1H), 7.13(d, J = 8.4 Hz, 1H), 7.01 (s, 1H), 6.07(s, 2H), 2.89–
2.84 (m, 2H), 1.81 (sext, J = 7.5 Hz, 2H), 1.00 (t, J = 7.5 Hz, 3H). 13C
2-Propyl-6-(trifluoromethyl)quinoline (3l) [12]. Dark yellow
NMR (75 MHz, CDCl3):
d
= 160.5, 150.4, 147.0, 146.0, 134.9, 123.3,
liquid (510 mg, 43%). 1H NMR (300 MHz, CDCl3):
d
= 8.07–8.01
(m, 3H), 7.77 (dd, J = 8.7, 2.1 Hz, 1H), 7.39 (d, J = 8.4 Hz, 1H), 2.93–
2.88 (m, 2H), 1.79 (sext, J = 7.5 Hz, 2H), 0.95 (t, J = 7.5 Hz, 3H). 13
119.4, 105.4, 102.5, 101.4, 40.9, 23.3, 14.0. Anal. Calcd. forC13H13NO2:
C, 72.54; H, 6.09; N, 6.51. Found: C, 72.17; H, 6.36; N, 6.17.
5,8-Dimethoxy-2-propylquinoline (3d). Pale yellow crystals
C
NMR (75 MHz, CDCl3):
d = 165.1, 149.2, 136.7, 130.0, 127.5 (q,
(438 mg, 37%). mp: 51 8C. 1H NMR (300 MHz, CDCl3):
d
= 8.37
2JC,F = 32.2 Hz, CF3-C), 125.4 (q, 3JC,F = 3.8 Hz), 124.9 (q,
1
(d, J = 8.7 Hz, 1H), 7.25 (d, J = 8.4 Hz, 1H), 6.82 (d, J = 8.4 Hz, 1H),
6.60 (d, J = 8.4 Hz, 1H), 3.94 (s, 3H), 3.85 (s, 3H), 2.96–2.91 (m, 2H),
1.77 (sext, J = 7.2 Hz, 2H), 0.94 (t, J = 7.2 Hz, 3H). 13C NMR (75 MHz,
3JC,F = 3.0 Hz), 124.1 (q, JC,F = 270.0 Hz, CF3), 122.6, 111.5, 41.3,
23.0, 13.8. 19F NMR (188 MHz, CDCl3)
d
= À60.3. HRMS m/z = calcd.
for C13H13F3N [M+H+]: 240.1000; found: 240.1004.
CDCl3):
d
= 162.4, 149.1, 148.7, 140.1, 130.9, 120.8, 120.0, 106.9,
2-Propyl-8-(trifluoromethyl)quinoline (3m) [12]. Dark yellow
102.8, 56.1, 55.6, 41.3, 23.3, 14.1. HRMS m/z = calcd. for C14H18NO2
[M+H+]: 232.1338; found: 232.1338.
8-Isopropyl-2-propylquinoline (3e). Yellow gum (590 mg, 55%).
1H NMR (300 MHz, CDCl3):
(m, 2H), 7.49–7.44 (m, 1H), 7.28 (d, J = 8.4 Hz, 1H), 4.44 (sept,
J = 6.9 Hz, 1H), 3.03–2.98 (m, 2H), 1.95 (sext, J = 7.5 Hz, 2H), 1.45 (d,
J = 6.9 Hz, 6H), 1.08 (t, J = 7.2 Hz, 3H). 13C NMR (75 MHz, CDCl3):
liquid (500 mg, 42%). 1H NMR (300 MHz, CDCl3):
d = 8.06 (d,
J = 8.4 Hz, 1H), 8.02 (d, J = 7.2 Hz, 1H), 7.93 (d, J = 8.1 Hz, 1H), 7.49
(t, J = 7.5 Hz, 1H), 7.35 (d, J = 8.7 Hz, 1H), 3.02–2.97 (m, 2H), 1.92
(sext, J = 7.2 Hz, 2H), 1.04 (t, J = 7.2 Hz, 3H). 13C NMR (75 MHz,
d = 8.04 (d, J = 8.4 Hz, 1H), 7.65–7.60
CDCl3):
127.0, 124.3 (q, 1JC,F = 271.5 Hz, CF3), 124.0, 122.3, 41.0, 22.1, 13.8.
19F NMR (188 MHz, CDCl3)
d
= 163.7, 144.5, 135.8, 131.9, 127.8 (q, 2JC,F = 30 Hz), 127.2,
d
= À58.2. Anal. Calcd. for C13H12F3N: C,
d
= 161.1, 147.1, 145.9, 136.2, 126.8, 125.6, 125.3, 124.9, 121.1,
65.27; H, 5.06; N, 5.85. Found: C, 64.95; H, 5.24; N, 5.73.
41.3, 27.6, 27.1, 23.6, 22.7, 14.2. HRMS m/z = calcd. for C15H20
N
[M+H+]: 214.1596; found: 214.1598.
Acknowledgements
5,8-Dimethyl-2-propylquinoline (3f). Dark yellow liquid
(529 mg, 54%). 1H NMR (300 MHz, CDCl3):
= 1.05 (t, J = 7.5 Hz,
3H), 1.91 (sex, J = 7.2 Hz, 2H), 2.64 (s, 3H), 2.79 (s, 3H), 3.00
(t, J = 7.5 Hz, 2H), 7.20 (d, J = 9 Hz, 1H), 7.30 (d, J = 9 Hz, 1H), 7.42
(d, J = 9 Hz, 1H), 8.20 (d, J = 9 Hz, 1H). 13C NMR (75 MHz, CDCl3):
d
The Indo-French program IFCPAR (Project 3705-1) is thanked
for the PhD grant to KD. CV and PVB are grateful to the French
Ministry of Foreign Affairs for an ARCUS fellowship. Central Glass
Co. Ltd. is acknowledged for kind gift of HFIP.

98
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[15] D. Vuluga, J. Legros, B. Crousse, A.M.Z. Slawin, C. Laurence, P. Nicolet, D. Bonnet-
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