Superacidic Cyclization of Activated Anthranilonitriles into 2-Unsubstituted-4-aminoquinolines

Article abstract of DOI:10.1021/acs.orglett.7b01798

4-Aminoquinolines were prepared in a three-step synthesis starting from substituted anthranilonitriles. The condensation on 1,1,1-trichloro-4-ethoxybut-3-enone proceeded efficiently either neat or in refluxing EtOH. Cyclization in superacidic trifluoromethanesulfonic acid provided unstable intermediate, which upon treatment with NaOEt in ethanol, afforded the expected esters. Theoretical investigations pointed out a monoprotonated nitrilium as the reactive species during the cyclization process.

Full text of DOI:10.1021/acs.orglett.7b01798

Letter
pubs.acs.org/OrgLett
Superacidic Cyclization of Activated Anthranilonitriles into
2‑Unsubstituted-4-aminoquinolines
Hubert Lavrard,† Paolo Larini,*,‡ and Florence Popowycz*,†
†Universite
‡Universite
́
́
Lyon 1, CNRS, INSA, CPE, UMR 5246, ICBMS, COB, 20 Avenue Albert Einstein, F-69621 Villeurbanne Cedex, France
Lyon 1, CNRS, INSA, CPE, UMR 5246, ICBMS, ITEMM, 43 Bd du 11 novembre 1918, F-69622 Villeurbanne, France
S
* Supporting Information
ABSTRACT: 4-Aminoquinolines were prepared in a three-step synthesis starting from substituted anthranilonitriles. The
condensation on 1,1,1-trichloro-4-ethoxybut-3-enone proceeded efficiently either neat or in refluxing EtOH. Cyclization in
superacidic trifluoromethanesulfonic acid provided unstable intermediate, which upon treatment with NaOEt in ethanol, afforded
the expected esters. Theoretical investigations pointed out a monoprotonated nitrilium as the reactive species during the
cyclization process.
Scheme1. ElectrophilicPartnersInvestigatedfortheCoupling
hevalue of quinolines accounts for its abundant applications
1
Tin medicinal chemistry as antimalarial agents. The in-use
treatments are the administration of antimalarial drugs either
single (chloroquine, quinine, ...) or in combination such as
Artemether−Lumefantrine (Coartem) and Atovaquone−Pro-
guanil (Malarone). Quinine alkaloid was also an invaluable
scaffold for asymmetric inductions with the use of the
pseudoenantiomercouple (cinchonine/cinchonidine) asorgano-
catalyst in a large range of synthetic transformations (Figure 1).2
Recently, glycoconjugates of quinolines have been reported to
exhibit different biological activities (molecular probes, anti-
infective, antiproliferative, antiaggregant, or antioxidant).3 Be-
sides, the 4-aminoquinoline scaffold is also involved in other
bioactive compounds such as analgesics or acetylcholinesterase
inhibitors.4
quinolines.8 Apart from these methods, 4-alkylquinolines can
be obtained by a one-pot reaction of anilines and alkyl vinyl
ketones in the presence of InCl3·SiO2 under microwave
irradiation.9 Contrasting with the use of simple anilines as
starting materials, a significant number of synthetic methods start
After a nonexhaustive survey of the literature, most of the
reported syntheses of the quinoline nucleus (Conrad−Limpach,
Knorr, Combes) provided 2-substituted quinolines, including the
recent published studies using multicomponent reactions,5
rearrangement of pyrazole NHCs,6 orcyclization with ynamides.7
Gould−Jacobs reaction gives the opportunity to afford 2-
nonsubstituted quinolines. Unfortunately, this reaction generally
suffers from a lack of regioselectivity when starting from meta-
substituted anilines, impeding the access to 5-substituted
fromortho-substitutedanilinessuchasFriedlanderreaction(from
̈
ortho-aminosubstituted carbonyl compounds),10 Pfitzinger re-
action from isatin, or Niementowski modification from
anthranilic acids. In all these above strategies, nitrogen atom
and C4 position of the future quinoline are already settled on the
starting material, allowing thus a perfect control of the
regioselectivity. Faced with these pioneering works dating from
more than a century, many groups have described valuable
modifications of the synthesis of aminoquinolines starting from
ortho-substituted anilines including tandem reactions,11 carbene
rearrangements,12 ring-closing metathesis,13 multicomponent
reactions,14 and gold-catalyzed cyclizations.15 Unfortunately,
most of these reactions only give access to 2-substituted
Received: June 14, 2017
Figure 1. Chemical structures of valued quinolines.
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b01798
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Scheme 2. Addition of Anthranilonitriles on
Trichlorobutenone
Figure 2. Energy comparison between mono-, di-, and tri-cationic
intermediates (values of ΔG in kcal·mol−1).
quinolines. To our knowledge, literature procedures describing
the regioselective synthesis of 2-nonsubstituted quinolines
remain very uncommon.16
poor nucleophilicity of 1a due to the strong electron-withdrawing
effect of the nitrile group and poor electrophilicity of ethyl 3-
ethoxyacrylateimputabletotheethoxygroups. Whenthereaction
was performed with 3 equiv of NaH instead of SnCl4, 1,4-addition
on the acrylate, followed by elimination of EtOH was observed,
leading to the formation of the enamine in an increased yield of
50%. Due to these disappointing results mainly due to the push−
pull system of aminobenzonitrile scaffold, we decided to change
our strategy and persist more on the nature of the acrylate
reactant.
Developing a methodology combining a simple access to C2
nonsubstituted 4-aminoquinolines, starting from easily available
substrates would open a significant breakthrough in comparison
to reported reaction conditions. Anthranilonitrile 1a was
previously condensed on ethyl acetoacetate in the presence of
over stoichiometric SnCl4 affording ethyl 4-amino-2-methylqui-
noline-3-carboxylate in excellent yield.17 Unfortunately, repeat-
ing the same conditions with ethyl 3-ethoxyacrylate A only
provided the corresponding enamine in a poor yield of 21%. The
failure of this reaction could be attributed concomitantly to the
As a consequence, the nature of the leaving group was
investigated in order to improve the electrophilicity of the
coupling partners A−D. Whatever its nature (OEt, NMe2, I, or
Scheme 3. Cyclization Scope
B
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Figure 3. Reaction profile for the formation of quinoline involving dicationic (blue) and tricationic (red) pathways. Only the structures for the dicationic
pathway are displayed for clarity.
SO2Ph), refluxing anthranilonitrile in ethanol led to no
conversion (Scheme 1).
optimized conditions. Compounds 3a−k were isolated in modest
to good yields, depending on the substitution pattern. In the case
of 5-substituted compounds 3i−k, yields were significantly lower,
presumably due to the steric hindrance of the substituents/
electronic effects in comparison with nonsubstituted 3a
compound, or smaller fluorine atom present in 3h. Heterocyclic
pyrazolo[3,4-b]pyridine 3m was obtained in a moderate 43%
yield. Other heterocyclic molecules 2l, 2n, or 2o failed to be
cyclized in our set of reaction conditions.
Switching to 1,1,1-trichloro-4-ethoxybut-3-en-2-one E used as
a synthetic equivalent of ethyl 3-ethoxyacrylate provided the
enamine 2a in 92% yield (100% Z in CDCl3 due to intramolecular
H bonding network; ratio of Z/E = 40:60 in DMSO).
Conveniently prepared in a one-step literature procedure from
ethyl vinyl ether and trichloroacetyl chloride,18 its condensation
with anilines has already been described.19
The substrate scope was next examined under the optimized
conditions: stoichiometric ratio of both reagents in refluxing
EtOH [2 M] during 24 h (Scheme 2). Generally, in the case of
anthranilonitriles, excellent yields were obtained by simple
heating in ethanol, and products 2b−m were spontaneously
formed in satisfying yields (Scheme 2). Products 2a−o exhibit a
Z/E interversion of the enamine at room temperature. The ratio
Z/E depends on the NMR solvent, with a global tendency to have
100%inCDCl3 androughlya Z/E ratio of 2:3inDMSO-d6. In the
special cases of electron-deficient or crowded anthranilonitriles
2f, 2g, 2m, and 2o, neat conditions at 100 °C were required to
reach full conversion.
To understand the necessity of triflic acid as the reaction
medium, ab initio study of the conversion of 2a to 3a was
undertaken. Seminal studies of Olah et al.23 in the seventies
proved the importance of highly reactive dicationic electrophiles.
According to the work of Shudo,24 nitrile groups are in a
diprotonated state in pure triflic acid. Only this highly dicationic
intermediary is supposed to be electrophilic enough to participate
in acylation reactions, which is not possible with the classic
nitrilium intermediate. To establish if the same pathway was at
stake in our system, theoretical investigations at the DFT level
were performed. Differently from the system studied by Shudo,
our cyclization precursor 2a possesses in addition to a nitrile
group, a push−pull conjugated system, due to the presence of a
combined enamine (push) and COCl3 (pull) group.
One example of cyclization of enaminones similar to 2a into
aminoquinolines bearing a CF2Cl group in place of CCl3 in neat
trifluoromethanesulfonic acid was described by Med
́
ebielle et
At first we computed several acid−base reactions, to establish
which was the most probable species for a mono-, di-, and tri-
cationic intermediate (Figure 2). Between monocationic species,
the most stable species was A1−CO, followed by A1−CN. This
reflects the electron donating ability of the amine group that
delocalizes preferentially its lone pair toward the CO than to the
CN. Concerning the dicationic family, the most stable structure
by far shows both the CO and CN groups protonated, following
the trend observed above. The species possessing a diprotonated
nitrile group (A2−CN−CN) is very unfavorable. At last, for the
tricationic species, the most stable structure is the one having a
protonated CO and a diprotonated nitrile (A3−CO−CN−CN).
Bearing in mind that acids weaker than TfOH did not furnish the
expected cyclized product, we excluded the possibility of the
reaction occurring from a monocationic species.
al.,20 with yields not exceeding 34%.21 In our hands, running the
reaction in hot CF3SO3H (150 °C) as a solvent was the sole
efficient reaction condition. Neither basic conditions (NaOEt,
NaH, KOtBu, NaH/TMSCl) nor acidic conditions (SnCl4,
AcOH, MeSO3H, TFA, H2SO4, and Ac2O/H2SO4 essentially all
used as neat conditions) afforded the expected aminoquinoline
(complex mixtures were obtained for most of the above
conditions). Temperature of the reaction could not be decreased,
as an inseparable byproduct from the expected compound is
formed (this side-product was identified as 3H-quinazolin-4-one,
based on comparison of analytical data with those of the
literature).22 Refluxingcompound2aintolueneinthepresenceof
1 equiv of TfOH led to total recovery of unreactive starting
material. Unfortunately, the trichloroketone intermediates were
unstableand could not be isolated in high yields. Therefore, direct
treatment with NaOEt in EtOH converted the trichloromethyl-
ketones into stable and easily isolable ethyl esters 3 (Scheme 3).
The substrate scope was next examined under the above
Therefore, we computed both the dicationic and tricationic
pathway (Figure 3). Starting from the most stable dicationic
species A2−CO−CN, double bond isomerization25 from Z to E
leadstodiastereoisomer B2, whichundergoescyclizationthrough
C
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TS−B2 (ΔG = 24 kcal·mol−1), giving rise to the endoergic
intermediate C2 (ΔG = 21.9 kcal·mol−1). The latter leads to the
thermodynamically stable product D2 (ΔG = −67.4 kcal·mol−1),
through a series of prototropic rearrangements. In analogy, the
tricationic pathway starts with A3−CO−CN−CN, furnishing the
E isomer B3. In this case, due to the higher electrophilicity of the
diprotonated nitrilium, the cyclization reaction occurs through a
low lying transition state (TS−B3, ΔG = 12.9 kcal·mol−1), giving
rise at first to the product C3 and finally to D3.
In summary, the use of TfOH as a superacid induces a double
protonation, which excluded the monocationic pathway. The
dicationic pathway, possessing a monoprotonated nitrile, is in
accordance with the required experimental conditions (heating at
150 °C) and observed reaction times (3 min). The tricationic
pathway has a rate limiting step barrier of 12.9 kcal·mol−1
implying that the reaction should occur at room temperature.
Thelatter result isalso inaccordance withthe literature reports by
Shudo, where the cyclization occurred at room temperature.
Thus, no double protonation of nitrile is at stake in our system,
due to the presence of the push−pull functional group in the
molecule.
In conclusion, an efficient three-step synthesis of 4-amino-2-
unsubstituted quinolines has been developed starting from
anthranilonitriles. Complete regioselectivity was observed, open-
ing access to a wide range of quinoline derivatives despite of the
substitution pattern. This is a versatile strategy for the de novo
synthesis of the pyridine ring in such compounds, without the
need of a protecting or directing group strategy. Theoretical
investigations revealed that a mono-protonated nitrilium species
is at stake in this reaction. Limitations of this protocol for the
moment have been identified on heterocyclic scaffolds, and the
extension to other heterocycles is under investigation.
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S
TheSupportingInformationisavailablefreeofchargeontheACS
Publications website at DOI: 10.1021/acs.orglett.7b01798.
Experimental procedures, characterization data, copies of
1H NMR and 13C NMR of new compounds, and computed
structures (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: florence.popowycz@insa-lyon.fr.
*E-mail: paolo.larini@univ-lyon1.fr.
ORCID
(20) Med
Tetrahedron Lett. 2005, 46, 7817−7821.
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ebielle, M.; Hohn, S.; Okada, E.; Myoken, H.; Shibata, D.
Paolo Larini: 0000-0002-5435-1768
Florence Popowycz: 0000-0002-0297-295X
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instability of difluorochloroketones, following our observations on
trichloroketones.
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The authors declare no competing financial interest.
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Chemistry, 2nd ed.; Wiley VCH: NJ, 2009.
ACKNOWLEDGMENTS
Theauthors are indebtedtothe French Minister
for a grant to H.L. CCIR-ICBMS (UCBL) is gratefully
acknowledged for the allocation of computational resources.
■
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(25) Double bond isomerization occurs at room temperature, as
observed experimentally by 1H NMR spectroscopy, thus no transition
state has been computed for this step.
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DOI: 10.1021/acs.orglett.7b01798
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