Synthesis of Highly Functionalized 4-Aminoquinolines

Article abstract of DOI:10.1002/anie.201511385

A diverse set of highly substituted 4-aminoquinolines was synthesized from ynamides, triflic anhydride, 2-chloropyridine, and readily accessible amides in a mild one-step procedure. Diverse products: Electrophilically activated amides easily react with sulfonyl ynamides to yield a diverse range of substituted 4-aminoquinolines. The ynamides can be easily modified by Sonogashira processes or generated from dichloroenamide precursors. Any substituent can thus be introduced at the C3 position of the quinoline. 2-ClPy=2-chloropyridine, Tf₂O=triflic anhydride.

Full text of DOI:10.1002/anie.201511385

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International Edition: DOI: 10.1002/anie.201511385
German Edition: DOI: 10.1002/ange.201511385
Heterocycle Synthesis
Synthesis of Highly Functionalized 4-Aminoquinolines
Tim Wezeman, Sabilla Zhong, Martin Nieger, and Stefan Bräse*
Dedicated to Professor Dieter Enders on the occasion of his 70th birthday
Abstract: A diverse set of highly substituted 4-aminoquino-
lines was synthesized from ynamides, triflic anhydride,
2-chloropyridine, and readily accessible amides in a mild
one-step procedure.
and electrophilically activated amides. In contrast to other
methods, this approach allows for substitution at the C2 and
C3 as well as at the C5 to C8 positions. Furthermore, the
installed 4-amino group is accessible after deprotection, thus
providing further points of diversity (Scheme 1).
Q
uinolines are well known for their antimalarial proper-
ties,[1] with prominent examples including chloroquine, amo-
diaquine, and mefloquine (Figure 1). However, owing to the
increasing resistance towards these and other antimalarial
drugs[1a,2] and the spreading of resistant Plasmodium falcipa-
rum species,[3] the synthesis of new antimalarial agents is of
great importance.[2a,4]
Scheme 1. Synthetic diversity of the developed approach towards
4-aminoquinolines.
Quinolines can be made in several different ways. More
recently developed approaches for the formation of quino-
lines are based on the conversion of 2-alkynyl arylazides into
substituted 4-acetoxyquinolines under gold catalysis,[8] one-
pot InCl3/SiO2 catalyzed reactions towards 4-methylquino-
lines,[9] and the use of ring-closing metathesis to access
4-hydroxy- or 4-methylquinolines.[10] 4-Phenylquinolines are
accessible by a Yb(OTf)3 catalyzed multicomponent reac-
tion[11] or by a “green” solvent-free one-pot process between
2-aminoaryl ketones and aryl acetylenes.[12] 4-Aminoquino-
lines can be prepared by the reduction of quinoline-4-
phenylhydrazine,[13] by hypobromite oxidation of 2,3-dime-
thylquinoline-4-carboxyamides,[14] via a 4-chloroquinoline
precursor,[6a] by rearrangements of pyrazolium-3-carboxylates
via pyrazol-3-ylidene intermediates,[15] by reacting 2-(tri-
fluoromethyl)-4H-3,1-benzoxazinones with ynamines,[16] or
by an aerobic oxidative Pd-catalyzed imidoylative coupling
Figure 1. Pharmaceutically relevant isoquinoline and 4-aminoquinoline
derivatives.[4a,5]
4-Amino-substituted quinolines are of particular pharma-
ceutical interest,[4a,6] and over the years, several synthetic
routes to these compounds have been explored.[7] The main
drawback of a lot of the existing quinoline syntheses is the
difficulty of functionalization at the C2 and C3 positions.
Herein, we present the synthesis of a diverse array of new,
highly substituted 4-aminoquinolines from sulfonyl ynamides
[*] T. Wezeman, Dr. S. Zhong, Prof. Dr. S. Bräse
Institute of Organic Chemistry (IOC)
Karlsruhe Institute of Technology (KIT)
Fritz-Haber-Weg 6, 76131 Karlsruhe (Germany)
E-mail: braese@kit.edu
[17]
À
with double C H activation.
These approaches usually
Dr. M. Nieger
Laboratory of Inorganic Chemistry
University of Helsinki (Finland)
allow for some degree of functionalization on the quinoline
core, and with the 4-chloro precursor strategy, 4-aminoquino-
lines with a wide range of functional groups at the C5 to C8
positions have been synthesized and found to be promising in
antimalarial assays.[18] However, accessing both the C2, C3
and the C5 to C8 positions has remained a challenge thus far.
The key to our synthesis of 4-aminoquinolines is the
activation of the amides with a combination of triflic
anhydride[19] (Tf2O) and 2-chloropyridine (2-ClPy), a proce-
dure used by Movassaghi and co-workers to prepare a wide
Prof. Dr. S. Bräse
Institute of Toxicology and Genetics (ITG)
Karlsruhe Institute of Technology (KIT)
Hermann-von-Helmholtz-Platz 1, 76344 Eggenstein-Leopoldshafen
(Germany)
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under http://dx.doi.org/10.
1002/anie.201511385.
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range of pyridine, pyrimidine, and b-carboline derivatives.[20]
While exploring the scope of this transformation, they were
also able to prepare a few 3-phenyl-4-oxazolidinone-based
4-aminoquinolines. Our approach, however, encompasses
a modular ynamide approach, providing full flexibility with
regard to substitution at the C2 and C3 positions as well as
indirect access to the 4-amino position. Structurally related
1-aminoisoquinolines have recently been synthesized by
employing a similar approach; silver triflate was employed
to cyclize 2-alkynylbenzaldoximes, which were then trans-
formed into 1-aminoisoquinolines in the presence of Tf2O and
2-fluoropyridine-activated amides in a domino fashion.[21]
To investigate the synthesis of 4-aminoquinolines, first,
several sulfonyl ynamides were prepared.[22] These can
generally be accessed by attaching acetylene derivatives
onto sulfonamides by copper[23] or iron[24] catalysis, by
copper-catalyzed alkynylative cross-couplings of 1,1-dibro-
moalkenes with sulfonamides,[25] or by the formylation of
sulfonamides followed by dibromomethylenation and subse-
quent elimination to the ynamide.[26] We proceeded by
protecting tosylamines by a reductive amination with a ben-
zaldehyde derivative or furfural[27] or by reacting benzylamine
with tosyl chloride; one of the prepared amides was analyzed
by X-ray crystallography (61; for details see the Supporting
Information). An acetylene bromide was then coupled with
the desired sulfonamide in the presence of copper sulfate
(0.1 equiv), 1,10-phenanthroline (0.2 equiv), and potassium
carbonate as the base. We thus prepared 14 different
ynamides in good to reasonable yields (see Figure 2,
route A). One of the prepared ynamides was analyzed by
X-ray crystallography (7; for details see the Supporting
Information). Similar ynamide systems were recently also
employed in gold-catalyzed [2+2+2] cycloadditions for the
formation of 4-aminopyrimidines.[28]
anilines or using conventional peptide chemistry. The amides
were activated with Tf2O and 2-chloropyridine at À788C,
before they were reacted with ynamides at 08C to form
quinolines. The optimized conditions for this transformation
were identified by performing a series of experiments
(Table 1). It was found that increasing the activated amide/
ynamide ratio yielded larger amounts of side products,
resulting in very complicated isolation.
Table 1: Selected examples for the optimization of the reaction con-
ditions for the generation of 4-aminoquinolines by amide activation.
R1
R2 Amide
[equiv]
2-ClPy Tf2O
[equiv] [equiv] [equiv]
Ynamide T[a]
Yield[b]
[8C] [%]
OMe
OMe
OMe
OMe
H
H
H
H
H
H
H
H
H
H
H
H
H
1.0
1.3
1.3
1.3
1.0
1.3
1.3
1.2
1.3
1.3
2.6
1.2
1.3
1.3
1.2
1.3
1.3
1.5
1.2
1.3
1.3
1.2
1.1
1.2
1.1
1.2
1.0
1.0
1.0
1.2
1.0
1.0
1.2
1.2
1.0
1.2
0
0
50
0
0
0
50
0
0
0
0
55
30
26
32
25
41
18
51
43
23
53
1.0; 4Š M.S. 1.2
Cl 1.0
Cl 1.3
Cl 1.0; 4Š M.S. 1.2
1.2
1.3
H
H
[a] The reaction mixtures were prepared at À788C and stirred at this
temperature for 5 min before they were stirred at the indicate temper-
ature; heating was facilitated by microwave irradiation. [b] Yields of
isolated products.
The acetylene bromides can easily be made on larger scale
(5 g) by bromination of the alkyne precursor with
N-bromosuccinimide with catalytic silver nitrate in acetone,
but care should be taken as some of the products were found
to be volatile.[23f] In order for the coupling to work as desired,
it was helpful to thoroughly grind the copper sulfate and 1,10-
phenanthroline before use. To synthesize an even greater
diversity of ynamides (and thus differently C3-substituted
quinolines), the corresponding terminal ynamide can first be
prepared by deprotecting the triisopropylsilyl-protected yna-
mide (to obtain 5–9, 16) and subsequently be converted in
a Sonogashira process (route B),[29] as shown for compounds
24–26. Alternatively, a procedure recently published by
Anderson et al.,[30] which involves the synthesis of a dichlor-
oenamide precursor and subsequent elimination and halogen
exchange, followed by quenching with a suitable electrophile
(route C) provides very convenient access to a wide range of
ynamides. Using this method, we were able to prepare larger
quantities of our ynamides with ease, but it must be stressed
that it is crucial to work under fully water-free conditions to
prevent the formation of a mixture of products (e.g., of the
desired ynamide and the terminal ynamide resulting from
hydrolysis).
Additionally, it was found that using the ynamide as the
limiting reagent did not always improve the conversion and
that an increased amount of 2-chloropyridine did not have
a clear beneficial effect. Heating the reaction was not
advantageous, but in some cases, the quinolines (e.g., 36 and
38) were still formed in reasonable yields (at 1208C under
microwave irradiation for 20 min). The best results were
obtained with the conditions originally proposed by Movas-
saghi and co-workers, with the additional use of activated 4 Š
molecular sieves to remove any traces of water (which is
detrimental to the reaction) and for consistent yields.
For the prepared 4-aminoquinolines to be useful from
a pharmaceutical point of view, it is highly desirable to be able
to deprotect the tosylated and benzylated amines with ease.
The free amines can then be used to prepare libraries for
screening purposes. However, conventional detosylation
reactions usually employ inelegant and harsh conditions,
such as lithium metal with catalytic amounts of naphthalene
at low temperatures,[31] that are unsuitable for more delicate
compounds. Fortunately, the tosyl group can be easily
removed according to the procedure recently reported by
Tomooka et al. and the use of potassium diphenylphos-
phide;[32] quinoline 62 was thus isolated in 79% yield
To explore the scope of the quinoline-forming reaction,
several different amides were synthesized by acetylating
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Figure 2. Modular synthesis of functionalized 4-aminoquinolines via ynamides prepared by A) copper catalysis, B) Sonogashira chemistry, or
C) elimination, lithium–halogen exchange, and quenching of the dichloroenamide intermediate with a suitable electrophile. E=electrophile,
NBS=N-bromosuccinimide, TBAF=tetrabutylammonium fluoride, TIPS=triisopropylsilyl.
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Scheme 2. Stepwise detosylation and debenzylation of the prepared
4-aminoquinolines.
(Scheme 2). Subsequently, the benzyl protecting group at the
4-amino position can be easily removed by hydrogenation
with wetted Pd/C (0.2 equiv) and a balloon of hydrogen gas at
room temperature for several days or by several iterations
using the H-Cube flow system with a Pd/C cartridge at 608C.
A quick solvent screen revealed that the reaction did not
proceed notably faster in ethanol or acetic acid. In an attempt
to find reaction conditions for faster deprotection, we
submitted N-benzyl-4-aminoquinoline to 20 bar of H2 with
0.2 equiv of dry Pd/C. As after three hours no promising
conversion was observed, we increased the catalyst loading to
1.1 equiv, and the reaction mixture was stirred overnight in
the pressure reactor. To our surprise, not only the N-benzyl
group was removed, but also the benzene ring of the quinoline
was reduced, and product 64 was thus obtained. The benzyl
group could also be removed first under identical conditions
with similar yields (91%), at which point the tosyl group can
be removed with SmI2.[33] Even though the tosyl deprotection
was observed to occur almost instantaneously (according to
LCMS and TLC), the potassium diphenylphosphide approach
was preferred because of reproducibility issues with the SmI2
route.
Figure 3. Molecular structures of the 4-aminoquinolines 46 (top) and
35 (bottom); ellipsoids set at 50% probability.
a diverse set of 4-aminoquinolines. The ynamides can be
easily modified by Sonogashira couplings or prepared via
a dichloroenamide precursor, which results in various sub-
stituents at the quinoline C3 position, and the choice of amide
allows for great diversity at the C2 and C5 to C8 positions.
Complex amides, for example, those derived from para-
cyclophanes, are also tolerated. Furthermore, the prepared 4-
aminoquinolines can be deprotected in excellent yields.[34]
Acknowledgements
X-ray crystal structures were obtained for two of the
synthesized quinolines, unequivocally confirming the struc-
ture and regiochemistry of the proposed products (Figure 3).
When quinoline syntheses with TIPS-protected ynamides
were attempted, the TIPS group was removed during the
reaction, and only quinolines with a proton at the C3 position
were obtained. As compound 60 can be obtained either from
the terminal ynamide in 67% yield or from the TIPS ynamide
in 14% yield, all other TIPS ynamides were also deprotected
before use. To show the broad applicability of this method, we
showed that the ynamides also readily react with paracyclo-
phane-based amides and thus yield compounds 43 and 44
creating very interesting planar chiral compounds, albeit in
a racemic manner. However, owing to issues with purification,
product 43 was obtained as a mixture with an inseparable side
product and 44 in rather low yield.
We acknowledge continuous funding from the DFG (BR
1750) and the Helmholtz association. T.W. would like to
acknowledge the Marie-Curie ITN ECHONET (316379).
Sarah C. Forcier and Nicolai A. Wippert are thanked for their
help during preliminary experiments. Dr. Stephen D. Lindell
(Bayer CropScience GmbH) is thanked for helpful discus-
sions.
Keywords: 4-aminoquinolines · heterocycles · ynamides
How to cite: Angew. Chem. Int. Ed. 2016, 55, 3823–3827
Angew. Chem. 2016, 128, 3888–3892
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Received: December 8, 2015
Published online: February 16, 2016
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