Letter pubs.acs.org/OrgLett
Direct Synthesis of 4‑Quinolones via Copper-Catalyzed Anilines and Alkynes Xuefeng Xu and Xu Zhang* College of Chemistry and Pharmaceutical Engineering, Nanyang Normal University, Nanyang 473061, China S Supporting Information *
ABSTRACT: A unique and direct approach for constructing 4quinolones from simple and readily available anilines and alkynes is described. Under the optimal conditions, both Nalkyl- and N-aryl-substituted anilines can be successfully transformed into the corresponding 4-quinolones. This reaction is characterized by mild reaction conditions, high functionalgroup tolerance, and amenability to gram-scale synthesis.
available anilines by C−H activation remains a challenging task (Scheme 1b). Furthermore, the cross-coupling reaction of anilines with dimethyl butynedioate for the synthesis of indoles catalyzed by palladium has emerged,7 and it has been noted that secondary enamines are generally inactive in palladiumcatalyzed C−H activation reactions.8 Inspired by this chemistry and as part of our ongoing project on the formation of heterocycles,9 we envisioned that the reaction of secondary amines and alkynoates would provide a general approach to quinolones by improving the electrophilicity of catalysts under acidic conditions (Scheme 1d). To test our hypothesis, we selected diphenylamine 1 and methyl phenylpropiolate 2 as the model substrates for reaction condition screening. The reaction was performed with Cu(OTf)2 catalyst and HOAc as additive, 120 °C for 12 h in DCE (Table 1, entry 1). Disappointingly, a trace amount of quinolone product 3l was detected. Thus, the additive species was screened first (entries 2−5). Gratifyingly, when HOTf was used, the desired quinolone product 3l was obtained in 89% yield (entry 2), while TsOH and Tf2O show no reactivity (Table 1, entries 3 and 4). Indeed, the yield of 3l was improved to 32% when TFA was used as an additive (Table 1, entry 5). No reaction was detected in the absence of catalyst Cu(OTf)2 or additive HOTf, which shows that Cu(OTf)2 and HOTf are essential in the course of the reaction (Table 1, entries 6 and 7). Other reaction media tested, including toluene, DMF, DMSO, CH3CN, MeOH, EtOH, Diox, and THF (entries 8−15), could not effect the desired transformation with a yield comparable to that in DCE. Finally, lowering the temperature to more benign 100 °C still enables the product formation with a reasonable yield (entry 16). With the optimized conditions established (Table 1, entry 2), we then studied the scope of the cyclization of methyl
4-Quinolones represent a major class of nitrogen-containing heterocycles that has been widely found in natural products, pharmaceuticals, and biologically active molecules.1 Therefore, the efficient synthesis of 4-quinolones has attracted the interest of chemists and pharmacologists. Classical methods such as Niementowski,2 Conrad−Limpet,3 and Camps cyclizations4 are based on cyclocondensation and suffer from harsh reaction conditions (high temperature and/or strong bases or acids), the limitation of substrate scope, unsatisfactory yields, and poor regioselectivities. Recently, several improved procedures for construction of a 4-quinolone framework to make use of transition-metal catalysis5 or ohaloaryl acetylenic ketones/amines or o-alkynylbenzamides/ aldehydes have been established (Scheme 1a).6 Despite significant advances, special starting materials such as orthohalogen/amino substitution substrates are required for the approach. The direct approach from simple and readily Scheme 1. Scope of Amines
Received: August 11, 2017 Published: September 7, 2017 © 2017 American Chemical Society
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DOI: 10.1021/acs.orglett.7b02495 Org. Lett. 2017, 19, 4984−4987
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Organic Letters Table 1. Condition Screening for the Synthesis of 1,2Diphenyl-4-quinolonea
entry
catalyst
additive
solvent
temp (°C)
yieldb (%)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
Cu(OTf)2 Cu(OTf)2 Cu(OTf)2 Cu(OTf)2 Cu(OTf)2 Cu(OTf)2
HOAc TfOH TsOH Tf2O TFA
DCE DCE DCE DCE DCE DCE DCE PhMe DMF DMSO CH3CN MeOH EtOH Diox THF DCE
120 120 120 120 120 120 120 120 120 120 120 120 120 120 120 100
trace 89 0 0 32 0 0 12 0 0 21 0 0 34 26 42
Cu(OTf)2 Cu(OTf)2 Cu(OTf)2 Cu(OTf)2 Cu(OTf)2 Cu(OTf)2 Cu(OTf)2 Cu(OTf)2 Cu(OTf)2
TfOH TfOH TfOH TfOH TfOH TfOH TfOH TfOH TfOH TfOH
Scheme 2. Copper-Catalyzed Intermolecular Cyclization of 2 with Different Anilinesa,b
a
Reaction conditions: 1 (0.5 mmol), 2a (0.6 mmol), Cu(OTf)2 (0.025 mmol), HOTf (0.025 mmol), in solvent (2 mL), 12 h. bYields of isolated products are given.
phenylpropiolate with a series of amines, as shown in Scheme 2. First, we examined the effect of the R1 substituent on the aromatic amine (Scheme 2, products 3a−h). In general, both electron-donating groups (EDGs) and electron-withdrawing groups (EWGs) on the phenyl ring were well tolerated to give the corresponding quinolones in good to excellent yields (67%−89%). All ortho-, meta-, and para-substituted anilines were smoothly transformed into the desired products, which indicated that steric bulk did not significantly affect the reactivity. To explore the substrate scope further, we examined the substituent effect of R2 moieties on this system. When R2 was an aliphatic group, such as −Me, −Et, −iPr, or −nBu, all of the substrates tested were smoothly convented to the corresponding quionlines (3a−j). Moreover, when 1,2,3,4tetrahydroquinoline was used as the substrate in this transformation, the 1,7-five-membered annulated quinolone 3l was obtained in 76% yield. Replacement of the aliphatic groups at the R2 position with aryl groups led to quinolones (3m−p) in somewhat higer yields. As expected, this reaction was not limited to simple aromatic amines, and the naphthalene substrates also afforded 3t and 3u in good yields with complete regioselectivity, respectively. In addition, this protocol is also applicable with active amino group remained intact under the reaction conditions (3v and 3w). Then our attention turned to explore the effect of substituents alkynes under the optimal conditions (Scheme 3). A variety of amines with an electron-withdrawing alkynyl ester (dimethyl butynedioate) gave the desired quinolones in excellent yields (4a−i). Gratifyingly, alkynyl ester substrates R3 (aliphatic and aryl groups) afforded moderate yields (4k− t). Alkynyl esters bearing 4-substituted electron-withdrawing groups (halogen and trifluoromethyl) were relatively sluggish and afforded moderate yields (4n, 4p, 4r, and 4s). Alkyl 4substituted alkynyl esters gave the desired quinolones in
a Reaction conditions: 1 (0.5 mmol), 2 (0.6 mmol), Cu(OTf)2 (0.025 mmol), HOTf (0.025 mmol), DCE (2 mL), 120 °C, 12 h. bIsolated yield after chromatography.
excellent yields (4o and 4q). Naphthyl, anthracenyl, and phenanthyl substrates participated efficiently as well to give the corresponding product (4v−x), which was obtained in a slightly lower yield, suggesting that the reaction was influenced by the steric effect. It is also worth noting that this protocol was readily scaled up to produce grams of quinolone 2a without loss of yield, demonstrating the practicability of this procedure (Scheme 4). To gain insight into the reaction mechanism, we carried out several control experiments (Scheme 5a). First, when the secondary enamine substrate 4 was subjected to the optimized conditions, the quinolone product was obtained in 92% yield, which showed that the enamines might be used as a key intermediate for the copper-catalyzed cascade reaction. At the same time, no quinolone 3l was discovered when the reaction was carried out in the absence of acid or Cu catalyst, which indicates that the acidic condition may be favorable for improving the electrophilic properties of the catalyst (Scheme 5b). On the other hand, if the quinolone product could obtain by reductive elimination, the oxidant must play an essential role in the catalytic cycle, and dioxygen is the only possible oxidant and an ideal oxidant.10 However, the reaction proceed smoothly under nitrogen atmosphene with an acceptable yield (Scheme 5c), which shows that deprotonation is much faster that reductive elimination. 4985
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Organic Letters Scheme 3. Copper-Catalyzed Intermolecular Cyclization of 1 with Different Alkynesa,b
Scheme 6. Proposed Mechanism for the Transformation
coordinated by the carbamoyl group of the enamine 5 and delivers the intermediate A;13 thus, a more electrophilic carbomyl moiety would lead to nucleophilic attack and, thus, directly protodemetalation to deliver the quinolone 3 and regenerate the catalyst. In conclusion, we have developed a unique and direct approach for constructing 4-quinolones from simple and readily available anilines and alkynes. Through this method, both N-alkyl- and N-aryl-substituted anilines can be successfully transformed into the corresponding 4-quinolones. The reaction conditions are mild, require manipulation, and do not require the addition of oxidizing agent, which provides an attractive methodology. Further scope investigation is ongoing and will be reported.
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ASSOCIATED CONTENT
S Supporting Information *
a Reaction conditions: 1 (0.5 mmol), 2 (0.6 mmol), Cu(OTf)2 (0.025 mmol), HOTf (0.025 mmol), DCE (2 mL), 120 °C, 12 h. bYield of the isolated product shown.
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b02495. Experimental procedures, characterization of products, and 1H and 13C NMR spectra (PDF)
Scheme 4. Gram-Scale Production of 1,2-Diphenyl-4quinolone
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Xu Zhang: 0000-0002-3588-3240
Scheme 5. Control Experiments
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We thank the Science Foundation of Nanyang Normal University (QN2016018) and the National Natural Science Foundation of China (21502100).
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REFERENCES
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