A microwave-assisted nucleophilic substitution reaction on a quinoline system: The synthesis of amino analogues of nitroxoline

Article abstract of DOI:10.1016/j.tetlet.2012.02.017

A reliable protocol for the synthesis of a series of 8-amino analogues of pharmacologically interesting nitroxoline (5-nitro-8-hydroxyquinoline) is described. The unprecedented displacement of the cyanomethoxy group of an O-cyanomethylated quinoline deriv

Full text of DOI:10.1016/j.tetlet.2012.02.017

Tetrahedron Letters 53 (2012) 1964–1967
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A microwave-assisted nucleophilic substitution reaction on a quinoline
system: the synthesis of amino analogues of nitroxoline
a,b,
⇑
c
Bogdan Štefane a,b, Franc Pozgan
, Izidor Sosic , Stanislav Gobec
ˇ
ˇ c
a
ˇ
Faculty of Chemistry and Chemical Technology, University of Ljubljana Aškerceva 5, SI-1000 Ljubljana, Slovenia
b EN?FIST Centre of Excellence, Dunajska 156, SI-1000 Ljubljana, Slovenia
c
ˇ
Faculty of Pharmacy, University of Ljubljana, Aškerceva 7, SI-1000 Ljubljana, Slovenia
a r t i c l e i n f o
a b s t r a c t
Article history:
A reliable protocol for the synthesis of a series of 8-amino analogues of pharmacologically interesting
nitroxoline (5-nitro-8-hydroxyquinoline) is described. The unprecedented displacement of the cyano-
methoxy group of an O-cyanomethylated quinoline derivative by various primary and secondary amines
selectively affords 5-nitroquinolin-8-ylamines in moderate-to-high yields. The reactions were acceler-
ated significantly under microwave conditions in comparison with conventional heating.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 30 December 2011
Revised 24 January 2012
Accepted 3 February 2012
Available online 11 February 2012
Keywords:
Quinolines
Nitroxoline
Cyanomethoxy group
Nucleophilic aromatic substitution
Microwave-assisted synthesis
The quinoline scaffold is prevalent in several natural and
synthetic compounds that display a broad range of biological
activities.1 For example, 8-aminoquinolines exhibit antimalarial2a
and antimicrobial2b behavior, whereas compounds containing the
hydroxyquinoline pharmacophore proved to be anti-tumor,3a,c
anti-fungal3b, and herbicidal3b agents. Furthermore, it was discov-
ered that the well-established anti-microbial agent, nitroxoline4
(5-nitro-8-hydroxyquinoline, 3) is a potent inhibitor of cathepsin
B, which is a promising therapeutic target as it participates in
the degradation of extracellular matrix proteins in tumor tissues.5
Moreover, nitroxoline has already shown promise as a potential
anti-angiogenic6a and anti-cancer agent,6b and 7-aminomethylated
derivatives (Mannich bases) of nitroxoline were examined for their
growth-inhibitory effect.7 Nitriles, on the other hand, are attractive
because of their biological robustness.8 A series of potent pepti-
domimetic cysteine cathepsin inhibitors containing C-terminal
nitriles have been developed.9
These facts have prompted us to design nitroxoline-derived
compounds. Initially, we planned to synthesize 8-cyanomethoxy-
7-aminomethylquinolines
1 starting from nitroxoline (3), as
O
CN
OH
O
CN
BrCH2CN
N
N
N
Cs2CO3
KNO3/H2SO4
r.t., 1 h
DMSO
r.t., 1 h
NO2
2
4
5
Scheme 2. Synthesis of O-cyanomethylated quinoline 2.
O
CN
N
N
O
CN
O
CN
NR1R2
O
CN
OH
1a
NO2
N
N
pyrrolidine
N
N
N
HCHO
EtOH, Δ, 20 h
2
NO2
1
2
NO2
NO2
3
NO2
N
Scheme 1. Retrosynthetic pathway to nitroxoline-derived compounds 1.
NO
7a
2
⇑
Corresponding author. Fax: +386 1 2419220.
E-mail address: franc.pozgan@fkkt.uni-lj.si (F. Pozgan).
ˇ
Scheme 3. Reaction of 2 with pyrrolidine under Mannich-reaction conditions.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2012.02.017

B. Štefane et al. / Tetrahedron Letters 53 (2012) 1964–1967
1965
depicted in Scheme 1, since this synthetic strategy would allow us
to incorporate a nitrile function into potentially active Mannich
bases of nitroxoline.
the expense of the hydrolyzed by-product. Therefore we applied
an efficient nitration procedure using a KNO3/H2SO4 mixture that
afforded the desired product 2 in an 85% yield (Scheme 2). To ob-
tain selectively the 5-nitro product 2 it was crucial that a minimum
amount of sulfuric acid was used and that the reaction was
quenched after a short time by the rapid introduction of cold
K2CO3 solution.
In order to obtain the 7-aminomethylated nitroxoline-derived
compounds of type 1 we investigated the Mannich reaction of the
O-cyanomethylated compound 2 with pyrrolidine in the presence
of formaldehyde, as has been reported for the aminomethylation
of nitroxoline.7 Surprisingly, instead of 1a we isolated only the
Unfortunately, the first step, the reaction of nitroxoline (3) with
bromoacetonitrile was not successful under the applied conditions,
probably due to the combined electronic effects of the nitro group
and the fused pyridine ring. Next, we found that 8-hydroxyquino-
line (4) reacted easily in the presence of Cs2CO3 with one equiva-
lent of bromoacetonitrile via its portion-wise addition to the
reaction mixture, giving the 8-cyanomethoxy product 5 in an
excellent yield of 91%. Standard nitration (HNO3/H2SO4) of 5 led
to the 5-nitro product 2 in a poor isolated yield (35%), mostly at
Table 1
Reactions of 2 with amines 6
NR1R2
O
CN
N
N
1 2
(6)
3 equiv. R R NH
7 NO2
2 NO2
Entry
1
R1R2NH
Solvent
Reaction conditions
Time
Product (yield;%)a
H
N
EtOH
MeCN
Reflux, standard heatingb
100 °C ( W, 150 W)
20 h
1 h
7a (88)
7a (89)
l
6a
H
N
EtOH
MeCN
Reflux, standard heatingb
100 °C ( W, 150 W)
20 h
1 h
7b (85)c
7b (76)c
2
l
O
6b
NH2
EtOH
EtOH
Reflux, standard heatingb
20 h
15 min
—
3
4
100 °C (
l
W, 80 W)d
7c (54)c
6c
Ph
Ph
NHMe
MeCN
100 °C (lW, 150 W)
1 h
7d (87)c
6d
NHMe
5
6
MeCN
MeCN
100 °C (
l
W, 150 W)
W, 150 W)e
1 h
2 h
7e (81)c
7f (85)c
6e
Me2NHÁHCl 6f
100 °C (
l
Ph
NH2
7
MeCN
100 °C (lW, 150 W)
2 h
7g (55)c
6g
H
N
8
MeCN
100 °C (lW, 150 W)
1.5 h
7h (58)c
CONEt2
6h
H
N
9
MeCN
100 °C (lW, 150 W)
2 h
7i (62)c
CO2Et
6i
H
N
10
11
MeCN
MeCN
100 °C (
l
W, 150 W)
W, 150 W)
2 h
2 h
7j (87)c
7k (32)c
Me
6j
NH2
N
100 °C (
l
6k
a
b
c
Yields of isolated products.
10 equiv of amine 6.
Product isolated by radial chromatography.
5 equiv of amine 6c.
2 equiv of NaHCO3 was added.
d
e

1966
B. Štefane et al. / Tetrahedron Letters 53 (2012) 1964–1967
8-aminoquinoline product 7a resulting from the nucleophilic dis-
placement of the cyanomethoxy group by pyrrolidine (Scheme 3). It
is worth mentioning that a reverse approach, the reaction of
7-aminomethylated nitroxoline with bromoacetonitrile, was not
successful.
significantly lower isolated yield of product 7g (55%) (Table 1, en-
tries 4–7). Piperidines 6h and 6i containing either amide or ester
functional groups afforded the 8-aminoquinolines 7h and 7i in
modest yields; 4-methylpiperidine, on the other hand, gave a much
higher yield of the amino product 7j (Table 1, entries 8–10). Sur-
prisingly, the reaction of 2 with pyridin-2-ylmethanamine (6k)
led to the product 7k in a disappointing isolated yield of 32% after
chromatographic purification (Table 1, entry 11). Although the
cyanomethoxy group could depart as formaldehyde and cyanide
ion, following the reaction by NMR spectroscopy we were not able
to detect such species [CAUTION!].18
In conclusion, we have demonstrated for the first time that a
cyanomethoxy group can serve as a good leaving group in nucleo-
philic aromatic substitution in a quinoline system. The microwave-
assisted displacement of the cyanomethoxy group of 8-cyano-
methoxy-5-nitroquinoline (2) by various primary and secondary
amines provided selectively the corresponding 8-quinolylamines
in moderate-to-high yields. Our methodology provides rapid ac-
cess to various 8-amino analogues of pharmacologically interesting
nitroxoline.
Quinolines bearing good leaving groups, such as halo-, meth-
oxy- or sulfonyloxy- are known to undergo aromatic nucleophilic
substitution with sulfur,10 oxygen,10c and nitrogen10c,11 nucleophiles.
Due to the very common presence of arylamine moieties in phar-
maceutically relevant compounds,2 methods for the amination of
(hetero)aromatics are of significant utility. It was reported that
the 8-dimethylamino group in highly activated 5,7-bis(trifluoro-
acetyl)quinoline could be replaced by various amines to afford
the desired 8-quinolylamines.12 Quinolylmethylamines were also
prepared by the oxidative methylamination of nitroquinolines,
but the method was rather unselective.13 On the other hand, the
Pd-catalyzed cross-coupling of 5- and 8-quinolyl halides and dif-
ferent amines (Buchwald–Hartwig reaction) provided efficiently
the corresponding 5- and 8-quinolylamines.14 To the best of our
knowledge, there are no examples of the cyanomethoxy group
acting as a leaving group in aromatic nucleophilic substitutions.
Thus, we focused our attention on the synthesis of 8-amino-5-
nitroquinoline derivatives 7, which actually represents the amino
analogues of nitroxoline, in order to take advantage of the displace-
ment of the cyanomethoxy group of quinoline 2 by nitrogen nucle-
ophiles. After optimization, the reaction of 2 with a large excess
(10 equiv) of pyrrolidine or morpholine in refluxing ethanol for
20 h afforded the products 7a and 7b in 88% and 85% yields,
respectively (Table 1, entries 1 and 2). While the reaction of 2 with
prop-2-yn-1-amine (6c) failed to provide the desired product 7c
under conventional heating for 20 h, substitution of the cyano-
Acknowledgments
The Ministry of Higher Education, Science and Technology of
the Republic of Slovenia and the Slovenian Research Agency (P1-
0230-0103) are gratefully acknowledged for their financial sup-
port. The study was performed and financed as a part of the
EN–FIST Centre of Excellence.
Supplementary data
methoxy group occurred with the use of microwave (lW) condi-
Supplementary data (synthetic procedures, spectroscopic and
analytical data for all compounds) associated with this article
can be found, in the online version, at doi:10.1016/
j.tetlet.2012.02.017.
tions. Thus, a fifteen-minute irradiation (power level 80 W) of an
ethanolic solution of quinoline 2 and five equivalents of amine 6c
provided N-(prop-2-ynyl)quinolin-8-amine 7c in a 54% isolated
yield (Table 1, entry 3). While the application of microwaves has
received much attention in organic synthesis,15 only a few exam-
ples of nucleophilic substitution in quinoline systems using micro-
wave irradiation have been described.10c,16 This encouraging result
prompted us to investigate the microwave-promoted nucleophilic
substitution reaction further.
In order to choose an appropriate solvent, the microwave-as-
sisted reaction of quinoline 2 and N-benzylmethylamine (6d) was
examined using CD3OD, DMSO-d6, and CD3CN as solvents, respec-
tively, at 100 °C (150 W) for 20 min. The crude product mixtures
were investigated by 1H NMR spectroscopy, which revealed that
the reaction in deuterated acetonitrile resulted in the formation
of the product 7d solely, whereas in methanol-d4 an unidentified
by-product was formed. In DMSO-d6, however, the quinoline 2
was not totally consumed. Therefore, acetonitrile was chosen as
the solvent for this reaction.
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were high (81–87%), the primary amine benzylamine (6g) gave a

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17. Typical procedure for the microwave-assisted synthesis of 5-nitro-8-
qunolinylamines 7:
(115 mg, 0.502 mmol), morpholine (131 mg, 1.5 mmol), and acetonitrile
(2 mL) was irradiated in a focused W reactor (Discover by CEM Corporation,
a mixture of 8-cyanomethoxy-5-nitroquinoline (2)
l
Matthews, NC) at 100 °C (150 W) for 1 h. The volatiles were evaporated and the
residue purified by radial chromatography (eluent: CH2Cl2/MeOH, 50:1) to give
99 mg (76%) of product 7b. Pale yellow crystals; mp 123.5–127 °C. IR (KBr,
cmÀ1) 3468, 3418, 2947, 2862, 2823, 1591, 1561, 1508, 1487, 1392, 1314,
1291, 1239, 1144, 1117, 1026, 980, 895, 829, 791, 741. 1H NMR (500 MHz,
CDCl3) d 3.68 (m, 4H), 4.03 (m, 4H), 7.03 (d, J = 9.0 Hz, 1H), 7.63 (dd, J = 9.0,
4.0 Hz, 1H), 8.46 (d, J = 9.0 Hz, 1H), 8.91 (dd, J = 4.0, 1.5 Hz, 1H), 9.26 (dd, J = 9.0,
1.5 Hz, 1H). 13C NMR (126 MHz, CDCl3) d 155.2, 148.0, 140.8, 137.6, 133.0,
127.4, 123.9, 123.6, 112.1, 66.9, 52.0. HRMS (EI+): calcd for C13H14N3O3 [M+H]+:
260.103, found: 260.102. Anal calcd for C13H13N3O3: C, 60.22; H, 5.05; N, 16.21.
Found: C, 59.74; H, 5.00; N, 15.97.
18. CAUTION: the reaction may produce HCN.