Letter pubs.acs.org/OrgLett
Superacidic Cyclization of Activated Anthranilonitriles into 2‑Unsubstituted-4-aminoquinolines Hubert Lavrard,† Paolo Larini,*,‡ and Florence Popowycz*,† †
Université Lyon 1, CNRS, INSA, CPE, UMR 5246, ICBMS, COB, 20 Avenue Albert Einstein, F-69621 Villeurbanne Cedex, France Université 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.
T
Scheme 1. Electrophilic Partners Investigated for the Coupling
he value of quinolines accounts for its abundant applications in medicinal chemistry as antimalarial agents.1 The in-use treatments are the administration of antimalarial drugs either single (chloroquine, quinine, ...) or in combination such as Artemether−Lumefantrine (Coartem) and Atovaquone−Proguanil (Malarone). Quinine alkaloid was also an invaluable scaffold for asymmetric inductions with the use of the pseudoenantiomer couple (cinchonine/cinchonidine) as organocatalyst in a large range of synthetic transformations (Figure 1).2 Recently, glycoconjugates of quinolines have been reported to exhibit different biological activities (molecular probes, antiinfective, antiproliferative, antiaggregant, or antioxidant).3 Besides, the 4-aminoquinoline scaffold is also involved in other bioactive compounds such as analgesics or acetylcholinesterase inhibitors.4 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 or cyclization with ynamides.7 Gould−Jacobs reaction gives the opportunity to afford 2nonsubstituted quinolines. Unfortunately, this reaction generally suffers from a lack of regioselectivity when starting from metasubstituted anilines, impeding the access to 5-substituted
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 from ortho-substituted anilines such as Friedländer reaction (from ortho-aminosubstituted carbonyl compounds),10 Pfitzinger reaction 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
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DOI: 10.1021/acs.orglett.7b01798 Org. Lett. XXXX, XXX, XXX−XXX
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Organic Letters 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).
poor nucleophilicity of 1a due to the strong electron-withdrawing effect of the nitrile group and poor electrophilicity of ethyl 3ethoxyacrylate imputable to the ethoxy groups. When the reaction 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. 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
quinolines. To our knowledge, literature procedures describing the regioselective synthesis of 2-nonsubstituted quinolines remain very uncommon.16 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-methylquinoline-3-carboxylate in excellent yield.17 Unfortunately, repeating 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 Scheme 3. Cyclization Scope
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Organic Letters
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.
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. 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. At first we computed several acid−base reactions, to establish which was the most probable species for a mono-, di-, and tricationic 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. 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 leads to diastereoisomer B2, which undergoes cyclization through
SO2Ph), refluxing anthranilonitrile in ethanol led to no conversion (Scheme 1). 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% in CDCl3 and roughly a Z/E ratio of 2:3 in DMSO-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. 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 Médebielle et 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 Refluxing compound 2a in toluene in the presence of 1 equiv of TfOH led to total recovery of unreactive starting material. Unfortunately, the trichloroketone intermediates were unstable and could not be isolated in high yields. Therefore, direct treatment with NaOEt in EtOH converted the trichloromethylketones into stable and easily isolable ethyl esters 3 (Scheme 3). The substrate scope was next examined under the above C
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Organic Letters 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. The latter result is also in accordance with the 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-2unsubstituted quinolines has been developed starting from anthranilonitriles. Complete regioselectivity was observed, opening 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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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b01798. Experimental procedures, characterization data, copies of 1 H NMR and 13C NMR of new compounds, and computed structures (PDF)
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AUTHOR INFORMATION
Corresponding Authors
*E-mail: fl
[email protected]. *E-mail:
[email protected]. ORCID
Paolo Larini: 0000-0002-5435-1768 Florence Popowycz: 0000-0002-0297-295X Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS The authors are indebted to the French Ministère de la Recherche for a grant to H.L. CCIR-ICBMS (UCBL) is gratefully acknowledged for the allocation of computational resources.
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REFERENCES
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DOI: 10.1021/acs.orglett.7b01798 Org. Lett. XXXX, XXX, XXX−XXX
