Transition-metal-free solid phase synthesis of 1,2-disubstituted 4-quinolones via the regiospecific synthesis of enaminones

Abstract

Herein, the transition-metal-free economical solid phase synthesis of 1,2-disubstituted 4-quinolones has been developed via the novel regiospecific synthesis of enaminones. Notably, a wide range of enaminones were synthesized via a silica-supported solid-phase reaction in good to excellent yields. The transformation of enaminones to 1,2-disubstituted 4-quinolones and N-methyl-2-aryl-4-quinolone alkaloid was achieved in high yield via an alumina-supported solid phase reaction. In addition, all the synthesized compounds were isolated directly in their pure form from the reaction mixture using an easy workup procedure.

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Introduction

In view of environmental and economic consciousness, the development of solid phase and transition-metal free reactions has been given considerable attention in the pharmaceutical industry. These types of reactions offer remarkable advantages, such as operational simplicity, avoidance of metal contamination in products, no work-up, minimum use of energy and saving manpower, which render the transformations more environmentally friendly. Therefore, pharmacists, as well as chemists,¹ are frequently involved in the development of greener strategies to replace toxic and flammable organic solvents by solid supports, such as inorganic oxides, and alumina or silica on which the organic compounds get adsorbed. Transition metal catalysed reactions are the most common tool in the formation of C–C, C–N, C–O and C–S bonds in conventional organic synthesis. In particular, bulk drug manufacturing industries distinctly use transition-metals to access required products; hence, these metals have the possibility of adsorption in the product in high concentrations and cause health risks in humans such as oxidative damage of DNA,² apoptosis,³ allergic dermatitis⁴ and inhibit the activity of steroidogenic enzymes.⁵ The purification of active pharmaceutical ingredients from transition metal catalysts is the major concern, which needs unnecessary protocols.⁶ Therefore, environmental friendly transition metal free, solid phase approaches are highly desirable for the synthesis of bioactive molecules.

In consideration of the biological importance of 4-quinolones as antimalarial,⁷ anticancer,⁸ and antimicrobial agents,⁹ which also exist as high pharmacological profile alkaloids (Fig. 1),¹⁰ numerous synthetic strategies have been reported for the construction of 1,2-disubstituted 4-quinolones.¹¹ Enaminones are one of the most common synthons utilised to access 4-quinolones, which include palladium or copper catalyzed cyclization of alkynones (Method A), chalcones (Method B) and enaminones (Method C), as shown in Scheme 1. However, the existing synthetic routes for both enaminones and 1,2-disubstituted 4-quinolones are associated with significant disadvantages such as the use of expensive transition-metal catalysts and corrosive acids, cumbersome procedures, and harsh reaction conditions. More importantly, none of the abovementioned reported methods afford deceptively simple looking 2-benzoyl substituted 4-quinolone scaffolds.

Fig. 1 Naturally occurring biologically active 1,2-disubstituted 4-quinolones.

Scheme 1 Synthetic approaches for 1,2-disubstituted 4-quinolones.

To tackle the abovementioned problems, we envisage a new synthetic protocol to synthesize 1,2-disubstituted 4-quinolones and their synthon, enaminones.

Enaminones (type A–C) (Fig. 2) are important building blocks for the construction of heterocycles in the field of medicinal chemistry. Enaminones of type A and B (Fig. 2) are utilized largely in the synthesis of fused quinolines,¹² pyrroles,¹³ pyrimidines,¹⁴ imidazoles,¹⁵ thiazoles,¹⁵ indoles,¹⁶ pyrazoles,¹⁷ triazoles,¹⁸ aminoalcohol¹⁹ and 4-quinolones,²⁰ whereas type C enaminones are less explored in synthetic chemistry.²¹ Because of their wide applications, enaminones are becoming versatile precursors in organic and medicinal chemistry.

Fig. 2 Types of enaminones.

Fig. 3 ORTEP diagram of molecule 13 at 50% probability.

Only a few methods have been reported for the synthesis of type A enaminones by reaction of aryl substituted ketene S,S-acetals with aromatic amines in the presence of stoichiometric amount of a strong base under reflux conditions^12a,22 (Scheme 2, a). Various methods are available in the literature for the preparation of enaminones of type B by reacting amines with β-dicarbonyl compounds,²³ α,β-ynones,²⁴ and monothio-β-diketones²⁰ (Scheme 2, b). Moreover, a few other methods have been reported such as the hydrolysis of amidines²⁵ and the reaction of β-dicarbonyl compounds with amines using microwave,²⁶ solvent free,²⁷ ionic liquid,²⁸ ultra sound²⁹ and water medium³⁰ conditions. Similarly, the synthesis of type C enaminones by the amination of α,β-unsaturated γ-dicarbonyl compounds,³¹ diaroylacetylenes,^21b α-tosyloxy acetophenones,³² phenacyl pyridiniumbromides³³ and 2-methylthio-substituted-1,4-enediones³⁴ have been reported. Majority of these methods for the synthesis of enaminones (type A–C) suffer from major disadvantages, such as the use of stoichiometric amounts of a strong base, high temperatures, formation of isomeric mixtures of enaminones, laborious synthetic routes to access the starting material in the presence of toxic solvents, which limit the utility of these protocols.

Scheme 2 Synthetic methods for enaminones.

In continuation of our ongoing research towards the development of new facile syntheses for both enaminones and biologically active 4-quinolones and to overcome the synthetic challenges of the abovementioned limitations, herein we successfully develop a robust transition-metal free, solid phase green synthetic strategy (Scheme 1, Method D and Scheme 2, C). All the synthesised compounds were isolated directly in their pure form from the reaction mixture via an easy workup procedure.

Results and discussion

In the beginning of our optimization reaction studies toward the synthesis of enaminones, ketene S,S-acetal (1a) and aniline (2a) were chosen as model substrates. These substrates were adsorbed on 5 volumes of neutral silica (60–120 mesh size) and heated at 80 °C for 12 h, but did not afford the desired ketene N,S-acetal (3a) (Table 1, entry 1) and the addition of the Lewis acid, anh. ZnCl₂ (0.5 equiv.), did not affect the reaction (entry 2). The addition of the more acidic Lewis acid, anhydrous AlCl₃ (0.05 equiv.), under similar reaction conditions afforded the desired enaminone (3a); albeit in low yield (20%, entry 3). Further attempts to improve the yield using basic or neutral alumina were not successful (entries 4 and 5). To view the influence of the acidic property of the solid support on the reaction, we adsorbed both reactants (1a and 2a) on acidic alumina at 80 °C, which afforded the desired product in 25% yield (entry 6). The reaction using the combination of acidic silica with 0.03 eq. anh. AlCl₃ at 60 °C afforded 3a in 78% yield (entry 7). Furthermore, to check the efficiency of other oxophilic Lewis acid catalysts on the reaction, we used 0.03 equiv. of SnCl₂·2H₂O, which resulted in enaminone 3a in 84% yield within 4 h at room temperature (entry 8).

Table 1 Optimization of reaction conditions

Entry^a	Solid support	Catalyst	Time (h)	Temp. (°C)	Yield^b (%)
a 1a (2.0 mmol), 2a (2.6 mmol), solid support (5 vol w.r.t 1a), catalyst (0.03 equiv.), and room temperature to 80 °C.b Isolated yields.c Starting substrates were recovered.
1^c	Neutral silica	—	12	80	0
2^c	Neutral silica	Anh. ZnCl2	12	80	0
3	Neutral silica	Anh. AlCl3	12	80	20
4^c	Basic alumina	Anh. AlCl3	12	80	0
5	Neutral alumina	Anh. AlCl3	12	80	10
6	Acidic alumina	Anh. AlCl3	12	80	25
7	Acidic silica	Anh. AlCl3	6	60	78
8	Acidic silica	SnCl2·2H2O	4	R.T	84

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The substrate scope of the solid phase reaction protocol (Table 1, entries 7 and 8) was examined by applying various aryl (heteroaryl) ketene S,S-acetals with different aromatic amines (Table 2). Electron donating –OMe substituents (1b, 1g, 1h) and electron withdrawing substituents, such as –Cl, and –CF₃, (1c, 1d, 1f) on the phenyl ring of ketene S,S-acetals were, competent to afford the desired products in high yields (58–79%). A noteworthy example is the reaction of aniline with ketene S,S-acetals having a pyridine entity (1j), which also proceeded well to afford 3j in good yield (54%).

Table 2 Synthesis of ketene N,S-acetal (enaminones, type A)^a,b

a Reaction conditions: 1 (2.0 mmol), 2 (2.6 mmol), acidic silica (5 vol w.r.t 1), anh. AlCl₃ (0.03 equiv.), 60 °C, and 6–8 h.b Yields in parentheses were obtained in the presence of SnCl₂·2H₂O (0.03 equiv.) at R.T for 4–6 h.

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To determine the efficiency of solid phase reactions towards the synthesis of enaminones, we continued our study by reacting aromatic amines (2) with unsymmetrical substituted β-(methylthio)-β-(het)arylenones (4) (Table 3)^20,35 on the stabilised solid phase (Table 1, entries 7 and 8). The substrates 4a and 4b afford the product 5a and 5b in excellent yield (79% and 74%), respectively, whereas a heterocyclic substituent at the β-position of enone (4c) gives the product (5c, 66%) in good yield. Aliphatic amines (2d–f) also gave enaminones (5d–f) in low to satisfactory yield (32–49%). However, in the presence of 0.05 equiv. anhydrous AlCl₃, the yield of 5e and 5f increased to 58% and 63%, respectively, after stirring at 60 °C for 24 h and the yield of 5d remained unchanged with the use of a higher equivalent (0.1 equiv. anh. AlCl₃) of catalyst.

Table 3 Synthesis of enaminones (type B)^a,b

a Reaction conditions: 4 (2.0 mmol), 2 (2.6 mmol), acidic silica (5 vol w.r.t 4), anh. AlCl₃ (0.03 equiv.), 60 °C, and 6–8 h.b Yields in parentheses were obtained in the presence of SnCl₂·2H₂O (0.03 equiv.) at R.T for 6 h to afford 5a–c and for 18–22 h to afford 5d–f.

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Furthermore, we extend our process to the synthesis of another important class of building blocks such as type C enaminones (Table 4). The starting substrates (6) were accessible easily from readily available aryl methyl ketones.³⁶ The reaction of 6a and 2a proceeded smoothly using stabilized conditions (Table 1, entry 7) to afford the product 7a in 75% yield (Table 4) after 12 h, but the reaction condition using acidic silica with SnCl₂·2H₂O (Table 1, entry 8) requires the temperature of 70 °C to give the product 7a (yield 82%, Table 4). Since these enaminones were investigated for the synthesis of biologically important 4-quinolones, we selected the optimized reaction condition of acidic silica/anh. AlCl₃ (Table 1, entry 7) for the synthesis of differently substituted enaminones of type C.⁴¹ The anilines with electron donating groups afforded enaminones in high yield as compared to the anilines having electron withdrawing groups (7c–f). Moreover, screening of substrates 6c–j revealed that more electron withdrawing groups on 6 decrease the amount of formation of 7c–j.

Table 4 Synthesis of enaminones (type C)^a,b

a Reaction conditions: 6 (2.0 mmol), 2 (2.6 mmol), acidic silica (5 vol w.r.t 6), anh. AlCl₃ (0.03 equiv.), 60 °C, and 12 h.b Yield in parentheses was obtained in the presence of SnCl₂·2H₂O (0.03 equiv.) at 70 °C for 8 h.

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We also attempted to explore a suitable combination of solid support and base for the cyclization of enaminone (7c) to access 1-aryl 2-benzoyl 4-quinolones (8c). We initially examined neutral alumina in the presence of 2 equiv. anh. K₂CO₃ as a base at 90 °C for 8 h, which afforded the product 8c; albeit in low yield (15%, Table 5, entry 1). The various combinations of acidic silica, neutral silica and basic alumina with different stoichiometric amounts of base did not give satisfactory results (entries 2–7). Furthermore, the use of basic alumina as a solid support with 3 equiv. anh. Cs₂CO₃ gave 8c in 55% yield (entry 8). Finally, the combination of basic alumina with 2 equiv. K₂CO₃ at 90 °C for 8 h was proven to be the best condition, where 7c underwent intramolecular cyclization to afford 8c in optimum yield (78%, entry 9).

Table 5 Optimization of the reaction on different solid supports

Entry^a	Solid support	Base	Time (h)	Yield^b (%)
a 7c (1.0 mmol), solid support (5 vol w.r.t 7c), base, 90 °C, and 8–12 h.b Isolated yields.
1	Neutral alumina	2 equiv. K2CO3	8	15
2	Neutral alumina	5 equiv. K2CO3	12	20
3	Neutral silica	3 equiv. K2CO3	12	10
4	Neutral silica	3 equiv. Cs2CO3	12	8
5	Acidic silica	3 equiv. Cs2CO3	12	0
6	Basic alumina	—	—	0
7	Basic alumina	2 equiv. LiOH	12	0
8	Basic alumina	3 equiv. Cs2CO3	12	55
9	Basic alumina	2 equiv. K2CO3	8	78

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Having established optimal conditions, we screened different types of enaminone 7 (Table 6) for cyclization toward 1-aryl 2-benzoyl 4-quinolones (8c–n). The electronic property of the substituent on aromatic amines influences the product yield. For instance, substrates 7d and 7f, which have electron donating substituents (–OMe) on aniline, give 1,2-disubstituted quinolones (8d and 8f) in higher yields than 7e, which have electron withdrawing substituents (–Cl). Similarly, the enaminones 7k–n, which have two extra –Cl atoms the on aromatic ring of the benzoyl moiety, afford the desired product 8k–n in a moderate yield (48–62%).

Table 6 Synthesis of 1-aryl 2-benzoyl 4-quinolone^a,b

a Reaction conditions: 7 (1.0 mmol), basic alumina (5 vol w.r.t 7), anh. K₂CO₃ (2 equiv.), 90 °C, and 8–10 h.b Substrates 6 were directly used for the synthesis of 4-quinolones without the purification of enaminones.

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Under similar optimized conditions, substrate 9 was adsorbed on basic alumina, with the addition of 2 equiv. K₂CO₃ and heated at 90 °C with vigorous stirring for 6 h, and product 10a–h was obtained in higher yields (80–94%).⁴² The percentage of yields of the products was compared with our previously reported method (Pd(OAc)₂/anh. Cs₂CO₃ in DMF), which is shown in parenthesis (Table 7).²⁰

Table 7 Synthesis of 1,2-diarylsubstituted 4-quinolones^a

a Reaction conditions: 9 (1.0 mmol), basic alumina (5 vol w.r.t 9), anh. K₂CO₃ (2 equiv.), and 90 °C for 6 h.

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We then became interested in the cyclization of the N-alkyl enaminones of type B (11) with 4-quinolone alkaloids (12), which have a high pharmacological profile. Thus, we successfully synthesised N-methyl-2-aryl-4-quinolone alkaloid (12a) found in the family Rutaceae in comparable yield to the reported methods³⁷ from the easily accessible enaminones via a catalyst and solvent free method (Scheme 3).

Scheme 3 Synthesis of N-alkyl 2-aryl 4-quinolones. Reaction conditions: 11 (1.0 mmol), basic alumina (5 vol w.r.t 11), anh. K₂CO₃ (2 equiv.), 90 °C, and 12 h.

To show the synthetic utility of 1-aryl 2-benzoyl 4-quinolones, 8d was subjected to iodination using iodine and ceric ammonium nitrate (CAN) in acetonitrile solvent³⁸ and 13 was obtained in excellent yield (92%, Scheme 4). The structure of 11 was confirmed by single crystal X-ray analysis (Fig. 3) and it will be an important synthon in many transition-metal catalyzed coupling reactions to obtain synthetically useful scaffolds.³⁸

Scheme 4 Iodination of 8d.

A single crystal of 13 with dimensions of 0.30 × 0.25 × 0.20 mm was chosen for X-ray diffraction studies. The crystal structure analysis showed that compound (13) crystallizes in an orthorhombic system under the space group Pbca, with cell parameters a = 8.7884(19) Å, b = 16.863(3) Å, c = 29.686(6) Å and Z = 8. The details of the crystallographic information have been deposited at the CCDC no 990917.³⁹

On the basis of the above experimental details (Tables 2–4), a possible mechanism is proposed in Scheme 5. Initially, acidic silica reacts with anh. AlCl₃ at 60 °C to generate strong Lewis acidic sites (SiOAlCl₂) on the surface of silica (I). Then, the starting substrate (II) is bound on the surface of (I) followed by the addition of amines at the β-position of the starting substrate (III). Finally, the product (IV) is released from the surface with the regeneration of (I).

Scheme 5 Proposed mechanism for enaminone formation.

On the basis of previous reports, wherein alumina supported K₂CO₃ is a hydrogen halide scavenger,⁴⁰ we propose a possible mechanism for the cyclization of type C enaminones in Scheme 6. On heating, basic alumina with anh. K₂CO₃ exposes the oxide and aluminium ions on the surface to type C enaminones through the loss of a water molecule. Thus, these active sites scavenge the hydrogen chloride from the enaminone adsorbed on the surface of alumina and it undergoes cyclization to 4-quinolones. Finally the used alumina and silica was treated using methanol and water.⁴³

Scheme 6 Proposed mechanism for the cyclization of enaminones.

Conclusions

We developed a new transition-metal-free method for the synthesis 1,2-disubstituted 4-quinolones and N-alkyl 2-aryl 4-quinolone alkaloids via the regiospecific synthesis of three different types of enaminones using a solvent free, green, solid phase protocol in good to excellent yield. This is the first method that reports the synthetically challenging 2-benzoyl 4-quinolones preparation in high yield. Our synthetic method is significant, due to the use of a less hazardous transition metal free reaction, solvent free (solid phase), easy work up procedures, and high yield of the products.

Acknowledgements

This study was supported by IOE, University of Mysore. ACV thanks CSIR (SRF-Ref: 9/119(0819)2KR-EMR-I) and KSV thanks the UGC-BSR for providing fellowship. MPS thanks the VGST Government of Karnataka for the award of Young Scientists for Research (SMYSR).

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41. Preparation of enaminones type A, B and C (3, 5 and 7): Appropriate substrate 1, 4, 6 (2 mmol), amine 2 (2.6 mmol) and 5 volume of acidic silica with respect to 1, 4, 6 was grinded thoroughly using a pestle and mortar (for liquid state reactants, a slurry was made using a small amount of chloroform under reduced pressure), and then transferred to an oven dried 30 mL screw cap reaction vial with a magnetic stir-bar, followed by the addition of anh. AlCl₃ (0.03–0.1 equiv.). The reaction mixture was stirred vigorously at 60 °C for the time mentioned in Tables 2–4. After completion of the reaction (monitored by TLC), the crude reaction mass was directly transferred to a column packed with silica gel and purified using ethyl acetate-hexane to give the desired product (3, 5 and 7).
42. Preparation of 1,2-disubstituted 4-quinolones (8, 10 and 12): The enaminones 7, 9 and 11 (1 mmol) were added to a mortar charged with basic alumina (5 volume), grinded thoroughly for 5 min, transferred to a dried 30 mL reaction vial with a magnetic stir-bar, followed by the addition of anh. K₂CO₃ (2 equiv.). The reaction mixture was stirred vigorously at 90 °C for the time mentioned in Tables 6, 7 and Scheme 3. After completion of the reaction, the crude reaction mass was subjected to silica gel column chromatography without any workup to give the desired product 8, 10 and 12.
43. Note: The alumina used was first treated with boiling methanol for 30 min of stirring, filtered through a Buchner funnel and washed with hot water followed by drying. Similarly, the silica used was stirred in a mixture of methanol and water (1 : 2) for 30–40 min, and then the silica gel was filtered through a sintered glass funnel and dried at 110 °C for 16 h.

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Footnote

† CCDC 990917. For crystallographic data in CIF or other electronic format see DOI: 10.1039/c5ra21421a

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