KHCO3- and DBU-Promoted Cascade Reaction to Synthesize 3-Benzyl-2-phenylquinolin-4(1 H)-ones

A novel and convenient one ‐ pot route for the synthesis of 3 ‐ benzyl ‐ 2 ‐ phenylquinolin ‐ 4(1 H) ‐ ones has been developed under transition ‐ metal ‐ free conditions. This new strategy features high yield and good functional group tolerance. In addition, a proposed mechanism has been confirmed for this reaction.

It′s very convenient: A convenient one ‐ pot route for the synthesis of 3 ‐ benzyl ‐ 2 ‐ phenylquinolin ‐ 4(1 H) ‐ ones has been developed under transition ‐ metal ‐ free conditions. This new strategy features high yield and good functional group tolerance.

• 4-quinolones; aldehydes; aldol reaction; cycloaddition; Michael addition
• 4 ‐ Quinolones, as an indispensable class of bicyclic structures, are frequently found in natural products and biologically active compounds (Scheme   [NaN] ). [7] They are also regarded as “privileged building blocks” for pharmaceutics in anticancer and antibiotic medicines.[8] In particular, 2 ‐ aryl ‐ 4 ‐ quinolones and their derivatives have been shown to be potential treatments for a range of diseases because they exhibit antiviral activities, antiplatelet,[14] antimalarial, xanthine oxidase,[17] cathepsins inhibitory activities and have positive cardiac effects.[21] For example, current research presents kinesin spindle protein (KSP) inhibitors as promising anti ‐ proliferative agents for cancer chemotherapy through potent antimitotic antitumor effects.[7] More recently, certain 3 ‐ benzyl ‐ 2 ‐ phenylquinolin ‐ 4(1 H) ‐ ones were evaluated and shown to have potent inhibitory activities in KSP ATPase.[7] Due to the “privileged” status, quinolones have attracted considerable attention in the development of practical synthesis.

Numerous synthetic strategies, especially Conrad ‐ Limpach, Niementowski reactions and transition ‐ metal ‐ catalyzed reactions including titanium ‐ mediated reductive coupling,[32] palladium ‐ catalyzed carbonylation, and ruthenium ‐ catalyzed reduction reactions,[35] have been developed to construct varieties of these valuable scaffolds. In 2007, Buchwald's group presented a base ‐ promoted synthetic methodology for 4 ‐ quinolones by using N ‐ (2 ‐ propionylphenyl) ‐ acetamide (Scheme   [NaN]  a).[36] In 2012, Pitchumani's group obtained 2 ‐ aryl ‐ 2,3 ‐ dihydro ‐ 4 ‐ quinolone from 1 ‐ (2 ‐ aminophenyl)ethan ‐ 1 ‐ one and aldehyde (Scheme   [NaN] , b).[37] Subsequently in 2015, Long's group reported a novel synthesis of diverse 2 ‐ aryl ‐ 4 ‐ quinolone derivatives via a TEMPO ‐ promoted intramolecular oxidative Mannich reaction (Scheme   [NaN]  c).[17] In this procedure, simple narylmethyl ‐ 2 ‐ aminophenyl ketones were used as starting materials. Nevertheless, compounds with only methyl or no functional groups at the C ‐ 3 position of 2 ‐ aryl ‐ 4 ‐ quinolone could be synthesized by this approach.

Although the synthetic routes of 4 ‐ quinolones have been well developed, in general they require multiple steps,[36] , [38] transition metal catalysts,[36] , and harsh reaction conditions, such as high temperature and strong acids. Moreover, various C ‐ 3 modified products are still difficult to form due to the inefficient preparation of starting materials. Herein, inspired by pioneering works, we have developed a novel route for the synthesis of 3 ‐ benzyl ‐ 2 ‐ phenylquinolin ‐ 4(1 H) ‐ ones from N ‐ (2 ‐ acetylphenyl) ‐ picolinamides and aldehydes under basic conditions. To our knowledge, transition ‐ metal ‐ free synthesis of 3 ‐ benzyl ‐ 2 ‐ phenylquinolin ‐ 4(1 H) ‐ ones has not been reported before.

Our initial efforts commenced with N ‐ (2 ‐ acetylphenyl) ‐ picolinamide 1 a and benzaldehyde 2 a as the model substrates in the presence of 2   equiv of K2CO3 at 100 °C for 10   h in DMSO, and the desired 3 ‐ benzyl ‐ 2 ‐ phenylquinolin ‐ 4(1 H) ‐ one 3 aa was able to isolated in 47 % yield (Table   [NaN] , entry   1). The structure of 3 aa was further confirmed by X ‐ ray crystallography.[45] Then the investigation of the solvent effects on the yield of the target product was carried out. Toluene and xylene failed to provide any useful conversions, and DMSO was superior to DMA and DMF (Table   [NaN] , entries   2–5). In order to find the best additives, we chose K2CO3, Na2CO3, KHCO3, NaHCO3, DBU, DABCO, Et3N and KOtBu as candidates; the results showed that KHCO3 was more favorable than other bases, the yield of 3 aa was increased to 55 % (Table   [NaN] , entries   1, 6–12). Gratifyingly, the yield of 3 aa was dramatically increased to 64 % by using the combination of KHCO3 and DBU as additive (Table   [NaN] , entry   13). Meanwhile, when the dosage of KHCO3 and DBU was increased to 2   equiv, the yield was improved to 71 % (Table   [NaN] , entries, 14). Further surveys of the reaction temperature indicated that 120 °C was beneficial for the formation of the desired product   3 aa and the yield was raised to 84 % (Table   [NaN] , entries, 15, 16). The investigation of reaction atmosphere showed that air was better than N2 and O2 (Table   [NaN] , entries   17, 18). Furthermore, the choice of an adequate reactant 1 for this conversion is evaluated. We attempted to use N ‐ acetyl, N ‐ benzoyl, N ‐ pyrazine ‐ 2 ‐ carbonyl, N ‐ 6 ‐ methylpicolinoyl, N ‐ 6 ‐ chloropicolinoyl amides and N ‐ H amine as reactants under standard conditions; the results showed that all these substrates could transform this reaction successfully with moderate yields. The highest yield was given when N ‐ picolinoyl amide was employed (Scheme   [NaN] ). These results matched well with the role of N ‐ aryl groups which stabilized the iminium intermediate and increased the yield. Finally, the optimized reaction conditions are as follows: N ‐ picolinoyl amide 1 (0.2   mmol), aldehyde 2 (3   equiv), KHCO3 (2   equiv) and DBU (2   equiv) in 1   mL of DMSO at 120 °C under air for 10   h.

Optimization of reaction conditions. [a]

1 [a]   Reaction conditions: 1 a (0.2   mmol, 1   equiv), 2 a (0.6   mmol, 3   equiv), additive (2   equiv), solvent (1   mL), 10   h. [b]   Isolated yields. [c]   Reaction was performed under N2 atmosphere. [d]   Reaction was performed under O2 atmosphere.

With the optimized reaction conditions in hand, we studied the scope of aldehydes in this reaction. As shown in Scheme   [NaN] , a diverse array of aldehydes, bearing electron ‐ donating, electron ‐ withdrawing or sterically hindered group substituted aromatic rings, and heterocycle ‐ aldehyde were examined. All of them underwent the reaction conditions smoothly and gave the corresponding products in excellent yields (Scheme   [NaN] , 3 aa–3 ay), ensuring a broad range of substrate scope. It can be seen clearly that the electron ‐ withdrawing groups exhibited more outstanding results in terms of providing the desired compounds than electron ‐ donating groups (Scheme   [NaN] , 3 ab–3 av), which indicated that electron ‐ withdrawing groups on the aromatic ring were more compatible with this reaction process. Furthermore, substrates having ethyl or aryl group at the para position of benzaldehyde also furnished the reaction in good yields (Scheme   [NaN] , 3 aj–3 ak). In addition, the reactions of benzaldehyde with substituents at the ortho, meta, and para positions were carried out, and the results showed that those with groups at the ortho position gave higher yields, followed by meta and para position (Scheme   [NaN] , 3 ab–3 ad, 3 af–3 ag, 3 al–3 an, 3 ap–3 at). Meanwhile, based on the results of benzaldehyde with mono or methyl or methoxy groups (Scheme   [NaN] , 3 ab–3 ai), the steric effect also has significant influence on the efficiency. Additionally, heteroaromatic and condensed ring structures were also able to produce the products efficiently (Scheme   [NaN] , 3 aw–3 ay), and 1 ‐ naphthaldehyde reacted excellently. However, an aliphatic aldehyde cannot be introduced into desired product by this protocol (Scheme   [NaN] , 3 az).

To further explore the applicability and compatibility of this synthetic route, we examined the scope of N ‐ (2 ‐ acetylphenyl)picolinamide under the same reaction conditions as shown in Scheme   [NaN] . Notably, a wide range of functional groups was tolerated well under the reaction conditions, such as methyl, methoxy, halogen, etc. Concerning the electronic effects of substituents on phenyl rings, the substrates bearing either electron ‐ withdrawing or electron ‐ donating groups afforded the desired products in good to excellent yields (Scheme   [NaN] , 3 ba–3 ma). The results also showed that the electron ‐ withdrawing groups were more effective for the transformation. Moreover, N ‐ (acetylphenyl)picolinamide bearing halogen substituents (Scheme   [NaN] , 3 ga–3 la) at meta position worked better than those at para position. The similar effects were also observed towards N ‐ (acetylphenyl) ‐ picolinamide with methyl substituents (Scheme   [NaN] , 3 ba–3 da).

To gain insight into the reaction mechanism, we carried out several control experiments (Scheme   [NaN] ). First, we carried out a reaction of 1 a and 2 a under the optimized conditions for 1.5   h, the desired product 3 aa was gained in low yield, whereas the intermediate 4 aa was harvested as the major product (Scheme   [NaN] , a). The structure of 4 aa was confirmed by X ‐ ray crystallography.[46] Then we performed the intermediate 4 aa under standard conditions and 4 aa could convert to 3 aa successfully, although the efficiency was not desirable (Scheme   [NaN]  b).

Based on the above results and previous literature, a plausible mechanism is suggested, as shown in Scheme   [NaN] . The reaction is initiated by the formation of intermediate   A through aldol reaction of 1 a and 2 a with addition of DBU and KHCO3. Then DBU and KHCO3 convert A to B by a hydrogen abstraction process, which may undergo intramolecular cyclization via the Michael addition to generate intermediate   C. Intermediate C further reacts through aldol reaction with 2 a to give the intermediate   D. The elimination of hydroxyl give intermediate   4 aa, and the isomerization of 4 aa affords E, which can hydrolyze to the desired product   3 aa.

In summary, a novel and efficient synthesis of 3 ‐ benzyl ‐ 2 ‐ phenylquinolin ‐ 4(1 H) ‐ ones has been developed for the first time by using 1 and 2 as starting materials under transition ‐ metal ‐ free conditions. This protocol has provided a broad substrate scope for the synthesis of 3 with good yields under mild conditions. Step economy and ease of operation make this transformation highly useful, which will promote the development of synthesis of natural products and pharmaceutics in anticancer and antibiotic medicines.

A test tube was charged with 1 a (0.2   mmol), 2 a (0.6   mmol), KHCO3 (0.4   mmol) and DBU (0.4   mmol) in DMSO (1   mL). Then the reaction mixture was stirred at 120 °C (oil bath temperature) under air atmosphere for 10   h. After cooling to room temperature, the solvent was extracted with ethyl acetate and washed with brine, dried with Na2SO4. After the solvent was evaporated in vacuo, the residues were purified by column chromatography, eluting with petroleum ether/ethyl acetate to afford pure 3 aa.

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Graph: Examples of bioactive compounds and natural products containing 4 ‐ quinolones.

Graph: image_n/asia201600901-fig-5001.png

Graph: Novel routes to synthesize 4 ‐ quinolones.

Graph: image_n/asia201600901-fig-5002.png

Graph: Synthesis of 3 ‐ benzyl ‐ 2 ‐ phenylquinolin ‐ 4(1 H) ‐ one 3 aa from different amide sources. [a]   Isolated yields of 3 aa

Graph: image_n/asia201600901-fig-5003.png

Graph: Synthesis of 3 ‐ benzyl ‐ 2 ‐ phenylquinolin ‐ 4(1 H) ‐ ones from substituted aldehydes and N ‐ (2 ‐ acetylphenyl) ‐ picolinamide.

Graph: image_n/asia201600901-fig-5004.png

Graph: Synthesis of 3 ‐ benzyl ‐ 2 ‐ phenylquinolin ‐ 4(1 H) ‐ ones from benzaldehyde and Substituted N ‐ (2 ‐ acetylphenyl)picolinamides.

Graph: image_n/asia201600901-fig-5005.png

Graph: Control experiments.

Graph: image_n/asia201600901-fig-5006.png

Graph: Proposed mechanism.

Graph: image_n/asia201600901-fig-5007.png

Graph: Supplementary