Rapid one-pot synthesis of antiparasitic quinolines based upon the microwave-assisted coupling-isomerization reaction (MACIR)

Article abstract of DOI:10.1055/s-2008-1032067

2-Substituted quinolines and related derivatives can be rapidly prepared from (hetero)aryl halides and propargyl alcohols in the sense of a one-pot microwave-assisted coupling-isomerization reaction (MACIR). First biological tests against trypanosomes and protozoans have revealed antiparasitic activity in the lower micromolar range. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1032067

LETTER
359
Rapid One-Pot Synthesis of Antiparasitic Quinolines Based upon the
Microwave-Assisted Coupling–Isomerization Reaction (MACIR)
a
a
b
b
a,1
A
O
ntiparasitic
Q
uin
a
olines by
M
n
icrowave-A
a
C
oupling–
G
Isomerization Re
a
.
ction (MAC
I
S
R) chramm, Thomas Oeser, Marcel Kaiser, Reto Brun, Thomas J. J. Müller*
a
Organisch-Chemisches Institut, Ruprecht-Karls-Universität Heidelberg, Im Neuenheimer Feld 270, 69120 Heidelberg, Germany
Schweizerisches Tropeninstitut, Socinstraße 57, Postfach, 4002 Basel, Switzerland
b
Received 5 November 2007
sical quinoline construction.10,11 An interesting access to
Abstract: 2-Substituted quinolines and related derivatives can be
rapidly prepared from (hetero)aryl halides and propargyl alcohols in
the sense of a one-pot microwave-assisted coupling–isomerization
2
-substituted quinolines makes use of a base-mediated
consecutive isomerization and cyclization sequence of 3-
reaction (MACIR). First biological tests against trypanosomes and (2-aminophenyl)-1-arylprop-2-yn-1-ols that are easily
protozoans have revealed antiparasitic activity in the lower micro- available by Sonogashira coupling of iodo aniline with
molar range.
propargyl alcohols after prolonged reaction time (7–20 h)
Key words: alkynes, antiparasitic activity, catalysis, cross-cou- at elevated temperature (180 °C), or upon using strong
1
2
plings, isomerizations, microwave reactions
bases (KOH). Recently, we have extended the coupling–
isomerization reaction (CIR),13 a straightforward enone
synthesis by Sonogashira coupling of (hetero)aryl halides
and propargyl alcohols with concomitant base-catalyzed
Quinolines represent an important class of heterocycles,
and the quinoline skeleton is present in various natural propargyl alcohol–enone isomerization, by dielectric
products, especially in alkaloids. Among them quinine is heating for electronically diverse substrates to a general
1
4
2
an active ingredient for the treatment of malaria. Despite microwave-assisted CIR (MACIR; Scheme 1). General-
its relatively low efficacy and tolerability, quinine still ly, the CIR is a suitable entry to multicomponent synthe-
plays an important role in the treatment of multiresistant ses of heterocycles.15 Here, we communicate an
malaria, one of the world’s most devastating infectious application of MACIR to the synthesis of antiparasitic
3
quinolines and first biological data.
diseases. Therefore, the design of many drugs and afford-
able chemotherapies are based upon synthetic quinoline
derivatives, such as chloroquine, mefloquine, quinacrine.4
In addition, chimanine alkaloids are also effective against
parasitic diseases such as leishmaniasis and trypanosomi-
PdCl2(PPh3)2 (2 mol%)
O
CuI (1 mol%)
I
PPh3 (20 mol%)
R
R'
THF
Et3N (5 equiv)
or
DBU (2 equiv)
MW (120–150 °C)
5
R
asis. Besides, leishmania-HIV co-infection has been re-
R = ERG, H, EWG
garded as an emerging infectious disease. Several 2-
+
62–96%
6
OH
substituted quinolines have been shown to possess in vit-
15–30 min
ro activity against causal agents of cutaneous leishmania-
sis, visceral leishmaniasis, African trypanosomiasis and
Caga’s disease as well as against HIV-1 replication. Thus,
substituted quinolines are generally attractive as antima-
larials, antibacterials, protein kinase inhibitors, NADH
models, and as agrochemicals. In addition, they are also
R'
H
OH
R'
R
coupling
7
interesting as ligands for transition-metal complexes as
8
well as general synthetic blocks. Numerous elegant syn-
alkyne–allene isomerization
theses have been developed for quinolines, however, the
exploration of diversity-oriented synthetic routes for this
class of compounds still remains a challenge. Quite some
syntheses of quinolines are based upon the condensation
of anilines, as the nitrogen component, and an electro-
OH
OH
Et3N
H
R
R
R'
R
+
HN Et3
philic three-carbon unit, such as in Skraup, in Doebner– Scheme 1 Microwave-assisted coupling–isomerization reaction
(
MACIR)
von Miller, in Combes, and in Conrad–Limpach
9
syntheses which are highly convergent. Even milder, re-
gioselective, and practical syntheses for these heterocy- In systematic studies on CIR accelerated by dielectric
cles can be envisioned by the aid of metal-catalyzed heating, we recently found that not only electron-with-
coupling circumventing the often harsh conditions in clas- drawing but also electro-neutral and even electron-rich
(
hetero)aryl halides can be successfully reacted propargyl
1
4b
SYNLETT 2008, No. 3, pp 0359–0362
x
x.
x
x.
2
0
0
8
alcohols in the sense of the CIR-chalcone synthesis. In-
deed, subjecting o-amino (hetero)aryl halides 1 and prop-
argyl alcohols 2 to the MACIR conditions, after 30
Advanced online publication: 23.01.2008
DOI: 10.1055/s-2008-1032067; Art ID: G35807ST
©
Georg Thieme Verlag Stuttgart · New York

3
60
O. G. Schramm et al.
LETTER
minutes reaction time, the corresponding quinoline deriv-
R
I
R
atives 3 were obtained in good to excellent yields
Pd(PPh3)2Cl2 (2 mol%)
CuI (1 mol%)
1
6,17
(
Scheme 2, Table 1).
Besides extensive spectroscopic
NH2
1
13
analyses ( H, C and DEPT, COSY, and HETCOR NMR
experiments, mass spectrometry) the structure was unam-
biguously confirmed by an X-ray crystal structure analy-
sis of the compound 3c (Figure 1).1
1
THF, DBU (2 equiv)
MW (120–150 °C)
N
R'
+
30 min
3
40–92%
OH
R'
8
2
Scheme 2 One-pot MACIR synthesis of 2-substituted quinolines
Table 1 MACIR Synthesis of 2-Substituted Quinolines 3a
Entry
2-Iodoaniline 1
Propargyl alcohol 2
Quinoline 3 (yield, %)b
I
1
2a R¢ = Ph
2b R¢ = 2-thienyl
2a
NH2
N
N
Ph
1
a
3a (81)
2
3
1a
S
3
b (80)
NC
I
NC
NH2
N
Ph
1b
3c (70)
NC
4
1b
2c R¢ = 4-MeOC H
6
4
N
OMe
3
d (57)
F3C
I
F3C
5
6
7
2a
NH2
N
Ph
1
c
3e (92)
1a
2d R¢ = trans-prop-1-enyl
N
3
f (40)
Me
I
Me
2a
N
NH2
N
N
Ph
1d
3g (79)
I
N
N
8
2a
2a
NH2
N
Ph
3
h (78)
1e
I
I
9
H2N
NH2
Ph
N
N
Ph
3
i (64)
1f
a
Reaction conditions: (hetero)aryl halide 1 (1.0 equiv), propargyl alcohol 2 (1.05 equiv), Pd(PPh ) Cl (0.02 equiv), CuI (0.01 equiv), DBU
3
2
2
(
2 equiv, 0.7 M in THF), heating in a sealed vessel at 150 °C in a Smith Synthesizer single-mode microwave cavity for 30 min.
Yields refer to isolated yields of compound 3 after flash chromatography on silica gel to be ≥95% pure as determined by NMR spectroscopy.
b
Synlett 2008, No. 3, 359–362 © Thieme Stuttgart · New York

LETTER
Antiparasitic Quinolines by Microwave-Assisted Coupling–Isomerization Reaction (MACIR)
361
References and Notes
(1) New address: Lehrstuhl für Organische Chemie, Institut für
Organische Chemie und Makromolekulare Chemie der
Heinrich-Heine-Universität Düsseldorf, Universitätsstraße
1, 40225 Düsseldorf, Germany.
(2) Wiesner, J.; Ortmann, R.; Jomaa, H.; Schlitzer, M. Angew.
Chem. Int. Ed. 2003, 43, 5274.
(
3) Gilles, M. H. Management of Severe Malaria: A Practical
Handbook, 2nd ed.; World Health Organization: Geneva,
Figure 1 Molecular structure of 3c
2000.
(
4) (a) O’Neill, P. M.; Mukhtar, A.; Stocks, P. A.; Randle, L. E.;
Hindley, S.; Ward, S. A.; Storr, R. C.; Bickley, J. F.; O’Neil,
I. A.; Maggs, J. L.; Hughes, R. H.; Winstanley, P. A.; Bray,
P. G.; Park, B. K. J. Med. Chem. 2003, 46, 4933.
Without isolation of intermediates, both the CIR and the
cyclocondensation take place in one step. Mechanistical-
ly, the formation of the quinoline core presumably occurs
via a base-mediated trans–cis isomerization equilibrium
under the microwave irradiation, followed by a conclud-
ing intramolecular condensation step. Interestingly, natu-
rally occurring quinoline alkaloids, such as 2-phenyl
quinoline (3a) or chimanine B (3f) can be prepared very
easily, very quickly, and in good yields. Starting with the
(b) Ridley, R. G.; Hofheinz, W.; Matile, H.; Jaquet, C.;
Dorn, A.; Masciadri, R.; Jolidon, S.; Richter, W. F.; Guenzi,
A.; Girometta, M. A.; Urwyler, H.; Huber, W.; Thaithong,
S.; Peters, W. Antimicrob. Agents Chemother. 1996, 40,
1
846. (c) Stocks, P. A.; Raynes, K. J.; Bray, P. G.; Park, B.
K.; O’Neill, P. M.; Ward, S. A. J. Med. Chem. 2002, 45,
975. (d) Vlahov, R.; Pavrushev, S.; Vlahov, J. Pure Appl.
4
1
,5-diamino 2,4-diiodobenzene (1f), in the sense of a
Chem. 1990, 62, 1303. (e) Madrid, P. B.; Sherrill, J.; Liou,
A. P.; Weisman, J. L.; DeRisi, J. L.; Kipling Guy, R. Bioorg.
Med. Chem. Lett. 2005, 15, 1015.
pseudo three-component reaction, the expected pyri-
doquinoline derivative 3i is accessible.
(
5) (a) Fournet, A.; Vagneur, B.; Richomme, P.; Bruneton, J.
Many quinolines have already been shown to possess an-
Can. J. Chem. 1989, 67, 2116. (b) Fournet, A.;
6
tileishmanial activity in vitro tests (IC = 12-100 mM).
5
0
Hocquemiller, R.; Roblot, F.; Cavé, A.; Richomme, P.;
Bruneton, J. J. Nat. Prod. 1993, 56, 1547. (c) Fournet, A.;
Barrios, A. A.; Muñoz, V.; Hocquemiller, R.; Cavé, A.;
Richomme, P.; Bruneton, J. Antimicrob. Agents Chemother.
Therefore, we have tested the 2-substituted quinoline de-
rivatives 3 at two concentrations with respect to their an-
tiparasitic
activity,
i.e.
against
trypanosomes
1993, 37, 859.
(
trypanosoma brucei rhodesiense, trypanosoma cruzi,
(
(
6) Fakhfakh, M. A.; Fournet, A.; Prina, E.; Mouscadet, J.-F.;
Franck, X.; Hocquemiller, R.; Figadere, B. Bioorg. Med.
Chem. 2003, 11, 5013.
leishmania donovani), and protozoans (plasmodium falci-
parum), all of them are responsible for the plagues of trop-
ical diseases such as sleeping sickness, leishmaniasis, or
malaria. Among the tested quinolines some representa-
tives display antiplasmodial activity at higher micromolar
levels. Therefore, the IC values against plasmodium fal-
7) (a) Steel, P. J. Coord. Chem. Rev. 1990, 106, 227. (b)Ernst,
S.; Kaim, W. J. Am. Chem. Soc. 1986, 108, 3578.
(c) Mamo, A.; Nicolleti, S.; Cam Tat, N. Molecules 2002, 7,
618. (d) Qaseer, H. Croat. Chim. Acta 2005, 78, 79.
5
0
(
8) Balasubramanian, M.; Keay, J. G. In Comprehensive
Hetrocyclic Chemistry II, Vol. 5; Katrizky, A. R.; Rees, C.
W.; Scriven, E. F. V., Eds.; Pergamon Press: Oxford, 1996,
Chap. 5.06, 245.
ciparum were determined for all quinoline derivatives 3.
The naphthyridine 3g showed also moderate activity
against plasmodium falciparum at lower micromolar con-
centration (IC 1.64 mg/mL).
5
0
(9) Manske, R. H. F.; Kukla, M. Org. React. 1953, 7, 59.
10) For a review on recent progress in the synthesis of
quinolines, see: Kouznetsov, V. V.; Mendez, L. Y.;
Mendelez Gomez, C. M. Curr. Org. Chem. 2005, 9, 141.
11) For recent quinoline syntheses, see e.g.: (a) Cho, C. K.; Oh,
B. H.; Shim, S. C. J. Heterocycl. Chem. 1999, 36, 1175.
(b) Cho, C. K.; Oh, B. H.; Shim, S. C. Tetrahedron Lett.
1999, 40, 1499. (c) Cho, C. K.; Oh, B. H.; Shim, S. C.; Oh,
D. H. J. Heterocycl. Chem. 2000, 37, 1315. (d) Cho, C. K.;
Oh, B. H.; Kim, J. S.; Kim, T.-J.; Shim, S. C. Chem.
Commun. 2000, 1885. (e) Sangu, K.; Fuchibe, K.; Akiyama,
T. Org. Lett. 2004, 6, 353. (f) Jacob, J.; Jones, W. D. J. Org.
Chem. 2003, 68, 3563. (g) Akiyama, T.; Nakashima, S.;
Yokota, K.; Fuchibe, K. Chem. Lett. 2004, 33, 922.
12) (a) Cho, C. S.; Lee, N. Y.; Kim, T.-J.; Shim, S. C.
J. Heterocycl. Chem. 2004, 41, 409. (b) Cho, C. S.
J. Organomet. Chem. 2005, 690, 4094.
(
In conclusion, we have developed a rapid and efficient
one-pot quinoline synthesis on the basis of MACIR of the
o-amino (hetero)aryl halides with propargyl alcohols
within 30 minutes and in good to excellent yields. First bi-
ological tests against selected parasites have revealed the
potential of new quinoline derivatives as antiparasitic
agents. Further studies directed to expand the synthetic
scope and the screening for compounds with higher activ-
ity are currently in progress.
(
Acknowledgment
(
Financial support of the Deutsche Forschungsgemeinschaft is gra-
tefully acknowledged. We also cordially thank Ms Annette Loos for
experimental assistance, Dr. Elisabeth Davioud-Charvet for valua-
ble discussions, and BASF AG for the generous donation of chemi-
cals.
(13) (a) Braun, R. U.; Ansorge, M.; Müller, T. J. J. Chem. Eur. J.
2006, 12, 9081. (b) Müller, T. J. J.; Ansorge, M.; Aktah, D.
Angew. Chem. Int. Ed. 2000, 39, 1253.
(
14) (a) Liao, W.-W.; Müller, T. J. J. Synlett 2006, 3469.
b) Schramm née Dediu, O. G.; Müller, T. J. J. Adv. Synth.
(
Catal. 2006, 348, 2565. (c) Schramm née Dediu, O. G.;
Müller, T. J. J. Synlett 2006, 1841.
Synlett 2008, No. 3, 359–362 © Thieme Stuttgart · New York

3
62
O. G. Schramm et al.
LETTER
(
15) (a) Müller, T. J. J. Targets in Heterocyclic Systems 2006, 10,
J = 2.1 Hz, 1 H). 13C NMR (100 MHz, CDCl ): d = 18.6
3
54. (b) Müller, T. J. J. Chim. Oggi/Chemistry Today 2007,
(CH ), 119.6 (CH), 121.3 (C ), 127.8 (CH), 128.8 (CH),
3
q
25(1), 70. (c) D’Souza, D. M.; Müller, T. J. J. Chem. Soc.
129.9 (CH), 131.5 (C ), 135.2 (CH), 137.1 (CH), 138.7 (C ),
q
q
Rev. 2007, 36, 1095.
16) Typical Procedure (3g, Table 1, Entry 7)
A magnetically stirred solution of 1d (234 mg, 1.00 mmol),
154.8 (C ), 155.8 (CH), 159.3 (C ). MS: (EI, 70 eV): m/z
q q
+
+
(
(%) = 220.1 (100) [M ], 205.1 (10) [M – CH ], 77 (12)
3
+
[C H ]. IR (KBr): n = 3027, 1604, 1581, 1546, 1503, 1481,
1458, 1434, 1321, 1278, 1140, 1025, 898, 814, 766, 739,
703, 678, 568 cm . Anal. Calcd for C H N (220.3): C,
6
5
2a (139 mg, 1.05 mmol), (PPh ) PdCl 20 mg, 0.02 mmol),
3
2
2 (
–
1
and CuI (2 mg, 0.01 mmol) in degassed DBU (2 mmol) and
THF (1.5 mL) was stirred under nitrogen in a heavy-walled
SmithCreator process vial in the microwave cavity at 150 °C
for 30 min. After cooling to r.t. EtOAc (40 mL) and H O (40
mL) were added and the aqueous layer was extracted with
EtOAc. The combined organic phases were dried with
15 12 2
81.79; H, 5.49; N, 12.72. Found: C, 81.71; H, 5.38; N, 12.79.
1
13
(17) All compounds have been fully characterized by H, C and
DEPT, COSY, NOESY, HETCOR and HMBC NMR
experiments, IR, mass spectrometry, HRMS, and/or
combustion analyses.
2
MgSO and the solvents were removed in vacuo. The residue
was chromatographed on silica gel (hexane–EtOAc, 5:1) and
(18) CCDC-669319 (3c) contains the supplementary
crystallographic data for this paper. These data can be
obtained free of charge via http://www.ccdc.cam.ac.uk/
conts/retrieving.html [or from the Cambridge
Crystallographic Data Center, 12 Union Road, Cambridge
CB2 1EZ, UK; fax: +44 (1223)336033; or
4
recrystallized from EtOH or pentane–CHCl (1:1) to give
3
1
1
74 mg (79%) of 3g as light yellow crystals, mp 142 °C. H
NMR (300 MHz, CDCl ): d = 2.54 (s, 3 H), 7.44–7.54 (m, 3
3
H), 7.91 (d, J = 1.5 Hz, 1 H), 7.94 (d, J = 8.3 Hz, 1 H), 8.13
(
d, J = 8.3 Hz, 1 H), 8.28 (dd, J = 8.3, 1.5 Hz, 2 H), 8.96 (d,
deposit@ccdc.cam.ac.uk].
Synlett 2008, No. 3, 359–362 © Thieme Stuttgart · New York

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