Ugi-Smiles couplings of 4-substituted pyridine derivatives: A fast access to chloroquine analogues

Article abstract of DOI:10.1021/ol202974w

4-Hydroxy and mercapto pyridines were successfully tested in Ugi-Smiles couplings. Such multicomponent reactions applied to quinoline derivatives afford a very convenient and short synthesis of antimalarial analogues.

Full text of DOI:10.1021/ol202974w

ORGANIC
LETTERS
2012
Vol. 14, No. 2
476–478
UgiÀSmiles Couplings of 4-Substituted
Pyridine Derivatives: A Fast Access to
Chloroquine Analogues
Laurent El Ka¨ım,* Laurence Grimaud,* and Patil Pravin
DCSO-UMR 7652: CNRS-ENSTA-Ecole Polytechnique, Laboratoire Chimie et
ꢀ ꢀ
Procedes, Ecole Nationale Superieure de Techniques Avancees, 32 Bd Victor,
75739 Paris Cedex 15, France
ꢀ
ꢀ
laurent.elkaim@ensta-paristech.fr; grimaud@dcso.polytechnique.fr
Received November 4, 2011
ABSTRACT
4-Hydroxy and mercapto pyridines were successfully tested in UgiÀSmiles couplings. Such multicomponent reactions applied to quinoline
derivatives afford a very convenient and short synthesis of antimalarial analogues.
The aminoquinoline motif isa prominent feature of anti-
malarial pharmacophores, as for instance in chloroquine,
primaquine, or amodiaquine (Scheme 1). Malaria is the
Scheme 1. 4-Hydroxy Pyridines in UgiÀSmiles Coupling
fifth leading cause of death from infectious diseases world-
wide and the second in Africa.1 The emergence of multidrug-
resistant falciparum malaria creates continuing demand
for new biologically active compounds. Multicomponent
reactions (MCRs) constitute very efficient synthetic tools
to generate diversity.2 Chibale and co-workers have re-
cently employed a Ugi coupling of 4-aminoquinolines to
This UgiÀSmiles (US) reaction, initially developed using
electron-deficient phenols as acidic partner,4 was soon
after extended to hydroxy heterocyclic compounds, such as
2-hydroxy pyridines, pyrimidines,5 and pyrazines6 (Scheme 2).
In connection with our ongoing projects on extending the
scope of this new isocyanide-based MCR, we envisaged a
high modular synthesis of aminoquinolines by assembling
the quinoline moiety and the amine in the key step.
The formation of antimalarial quinolines using UgiÀSmiles
couplings requires the use of 4-hydroxy- or 4-mercapto-
substituted quinoline as starting material. However, following
our computational study of the UgiÀSmiles reaction with
synthesize new potential antimalarial compounds.3
A few years agon we reported a new Ugi-type coupling
for rapid access to aminoaryl and heteroaryl carboxamides.
(1) World Malaria Report 2010. http://whqlibdoc.who.int/publications/
2010/9789241564106_eng.pdf, accessed 21 June 2011.
€
(2) For reviews, see: Domling, A.; Ugi, I. Angew. Chem., Int. Ed.
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2000, 39, 3168–3210. Bienayme, H.; Hulme, C.; Oddon, G.; Schmitt, P.
€
Chem.;Eur. J. 2000, 6, 3321–3329. Ugi, I.; Werner, B.; Domling, A.
€
Molecules 2003, 8, 53–66. Domling, A. Curr. Opin. Chem. Bio. 2002, 6,
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306–313. Zhu, J.; Bienayme, H., Eds.; Multicomponent Reactions; Wiley-
€
VCH: Weinheim, Germany, 2005. Domling, A. Chem. Rev. 2006, 106,
17–89.
(3) Musonda, C. C.; Taylor, D.; Lehman, J.; Gut, J.; Rosenthal, P. J.;
Chibale, K. Bioorg. Med. Chem. Lett. 2004, 14, 3901–3905. Musonda,
C. C.; Gut, J.; Rosenthal, P. J.; Yardley, V.; de Souza, R. C. C.; Chibale,
K. Bioorg. Med. Chem. 2006, 14, 5605–5615. Musonda, C. C.; Little, S.;
Yardley, V.; Chibale, K. Bioorg. Med. Chem. Lett. 2007, 17, 4733–4736.
(4) (a) El Kaim, L.; Grimaud, L.; Oble, J. Angew. Chem., Int. Ed.
2005, 44, 7165–7169. (b) El Kaim, L.; Gizolme, M.; Grimaud, L.; Oble, J.
J. Org. Chem. 2007, 72, 4169–4180.
(5) El Kaim, L.; Gizolme, M.; Grimaud, L.; Oble, J. Org. Lett. 2006,
8, 4019–4021. (b) Barthelon, A.; Dos Santos, A.; El Kaım, L.; Grimaud,
L. Tetrahedron Lett. 2008, 49, 3208–3211.
¨
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Lett. 2008, 49, 3208–3211.
r
10.1021/ol202974w
Published on Web 12/29/2011
2011 American Chemical Society

Table 1. 4-Hydroxy Pyridine in UgiÀSmiles Coupling
Scheme 2. UgiÀSmiles Coupling Mechanism and Previous
Work
entry
R1
R2
R3
Cy
R4
yield (%)
1
2
3
4
5
6
7
i-Bu
i-Bu
i-Bu
i-Bu
Et
H
H
H
H
H
All
69
65
72
43
50
26
40
Cy
MeO(CH2)2
3,4-(MeO)2Ar(CH2)2
All
Cy
t-Bu
4-ClBn
4-ClBn
4-ClBn
HCCCH2
MeO(CH2)2
H
(CH2)4
nitrophenol, 4-substituted pyridines are expected to be less
reactive than their 2-analogues because of the existence of
potential hydrogen bonds in the reactive intermediates of the
latter.4b,7 As all reported UgiÀSmiles of pyridines and quino-
lines were perfomed on their 2-substituted derivatives, we
initiated this study by testing 4-hydroxy pyridine. For this
purpose, classical conditions were tested, and methanol was
selected as a solvent of choice to solubilize all the partners.
A stoichiometric amount of 4-hydroxy pyridine, cyclohexyl
isocyanide, allyl amine, and isovaleraldehyde heated for two
days at 65 °C affords the corresponding 4-amino pyridine in
69% isolated yield (Scheme 3).
i-Bu
H
The scope of the reaction was next examined varying the
other partners. As usually observed, ketones are less
reactive than aldehydes, and the yields do not exceed
30% (Table 1, entry 6). Various amines could be used.
Albeit less efficient, ammonia undergoes smooth coupling
under microwave irradiation.10
Table 2. 4-Hydroxyquinolines in UgiÀSmiles Coupling
Scheme 3. 4-Hydroxy Pyridines in UgiÀSmiles Coupling
entry
X
R1
R2
R3
yield (%)
1
2
3
4
5
6
7
8
9
CF3
CF3
CF3
CF3
H
Cy
Cy
i-Bu
All
All
All
71
36
69
36
46
60
47
49
7
4-ClPh
i-Bu
4-MeOBn
Cy
Surprisingly, 4-hydroxy pyridine undergoes smooth
couplings under these conditions, whereas 2-hydroxy pyr-
idine requires the presence of an electron-withdrawing
group to react.4a The difference of reactivity between both
regiomers is not easy to rationalize. It is worth noting that
4-hydroxy pyridine derivatives such as mesylates, tosy-
lates, or 4-halogeno pyridines generally require harsher
conditions for SNAr: high temperature and pressure8 or
catalyzed processes.9 In our case, an activation due to the
acidity of the hydroxy heterocycle or to the proticity of the
solvent cannot be excluded.
4-ClPh
i-Bu
MeO(CH2)2
All
Cy
H
4-MeOBn
4-MeOBn
Cy
i-Bu
MeO(CH2)2
All
H
i-Bu
H
i-Bu
4-ClBn
H
t-Bu
i-Bu
MeO(CH2)2
After these preliminary results with pyridines, we next
examined the behavior of quinolines to obtain new muti-
component access to antimalarial drugs. The reaction
performed in the same conditions affords the desired
adducts in satisfying yields with both 4-hydroxy quinoline
and the 2-trifluoromethyl-substituted one. Various alde-
hydes, amines, and isocyanides have been coupled success-
fully as listed in Table 2, except for tert-butylisocyanide.
ꢀ
(7) Cheron, N.; El Kaım, L.; Grimaud, L.; Fleurat-Lessard, P.
¨
Chem.;Eur. J. 2011, 17, 14929À14934.
(8) Kotsuki, H.; Sakai, H.; Shinohara, T. Synlett 2000, 116–118. Han,
Y. F.; Li, C. P.-L.; Chow, E.; Wang, H.; Pang, Y.-P.; Carlier, P. R.
Bioorg. Med. Chem. 1999, 7, 2569–2576.
(9) Mantel, M. L. H.; Lindhardt, A. T.; Lupp, D.; Skrydstrup, T.
Chem.;Eur. J. 2010, 16, 5437–5442. Shen, Q.; Ogata, T.; Hartwig, J. F.
J. Am. Chem. Soc. 2008, 130, 6586–6596. Liu, Z.-J.; Bolm, C.; Vors,
J.-P.; Gesing, E. R. F. Adv. Synth. Catal. 2010, 352, 3158–3162.
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2784–2788.
Org. Lett., Vol. 14, No. 2, 2012
477

This method seems to be quite appealing to obtain chlo-
roquine analogues, as the amine and the quinoline could
be linked via a four-component coupling. In order to
approach even closer to the structure of active drugs,
the amide moiety should be reduced. Borane-induced
reduction of Ugi adducts was reported by Tron and
Giovenzana.11 Unfortunately, the reduction of these ad-
ducts under their reported conditions failed to give any
diamine.
was next examined. In all cases, the US products were
isolated in excellent to good yields (Table 4), and the
desulfurization of thioamides afforded the corresponding
diamines with satisfying yields (Table 4).
Scheme 4. Two-Step Access to Aminoquinolines
Facing problems in the reduction step, we decide to
examine the behavior of the mercapto heterocycle ana-
logues. Their UgiÀSmiles couplings could form thioamides,
privileged functional groups for further synthetic trans-
formations. 4-Mercapto pyridine was first evaluated in
UgiÀSmiles couplings. The corresponding N-pyridino
thiocarboxamides were obtained in moderate to good
yields as displayed in Table 3. The resulting thiocarbox-
amides could be further transformed into diamines under
reductive conditions. In our case, the reduction could be
To conclude, 4-hydroxy and 4-mercapto pyridine deriv-
atives are efficient partners in UgiÀSmiles couplings, being
even more reactive than their 2-substituted analogues,
which require further activating groups. We devel-
oped an efficient and straightforward acess to 4-amino-
quinolines, which makes the method potentially attractive
for the synthesis of new antimalarial pharmacophores.
performed either using BH3 Me2S in THF or with Raney
3
Nickel in ethanol. The corresponding diamines, which
constitute N,N-dimethylaminopyridine analogues, were
isolated in good yields (Table 3).
Table 4. 4-Mercaptoquinoline in UgiÀSmiles Coupling
Table 3. 4-Mercaptopyridine in UgiÀSmiles Coupling
entry R1
R2
R3
US (%) desulfurization (%)
1
2
3
4
5
6
7
8
9
Cy i-Bu
Cy i-Pr
Cy
Pr
Pr
Pr
Pr
Pr
Pr
Bu
87
81
56
81
78
51
99
98
55
42
67
39
41
67
75
entry
R1
i-Bu
R3
R4
US (%) reduction (%)
H
t-Bu i-Bu
t-Bu i-Pr
t-Bu H
1
2
3
4
5
6
Cy
All
80
57
i-Bu
i-Bu
i-Bu
i-Bu
4-ClBn All
Cy
Cy
Cy
MeO(CH2)2
Ph(CH2)2
Pr
55
60
55
34
60a
73a
76a
Cy i-Bu
Cy i-Bu
Cy i-Bu
Ph(CH2)2
MeO(CH2)2 82
4-ClC6H4 Cy
MeO(CH2)2
10 Cy 4-ClPh
11 Cy 3,4,
Pr
89
64
37
a The yields are given for condition A, except for entry 3 tested under
the two reductive conditions: A 60% and B 59%.
Ph(CH2)2
5-(MeO)3Ph
The whole sequence was then tested using the 4-mercap-
to-2-trifluoromethylquinoline. The reduction of the crude
US adduct with borane gave a complex mixture, but the
attempted aminoquinoline was isolated in 46% over two
steps by treatment with Raney Nickel in ethanol at 55 °C
for 30 min to 1 h (Scheme 4). The scope of this sequence
Acknowledgment. P.P. thanks the ANR-CP2D Pro-
gram (ANR MUSE) for a fellowship. We thank Dr
G. C. Tron for helpful discussions.
Supporting Information Available. Experimental pro-
cedures and spectral data for new compounds are de-
tailed. This material is available free of charge via the
Internet at http://pubs.acs.org.
(11) Pirali, T.;Callipari, G.;Ercolano, E.;Genazzani, A. A.;Giovenzana,
G. B.; Tron, G. C. Org. Lett. 2008, 10, 4199–4202.
478
Org. Lett., Vol. 14, No. 2, 2012