DMAP-Catalyzed Reaction of Diethyl 1,3-Acetonedicarboxylate with 2-Hydroxybenzylideneindenediones: Facile Synthesis of Fluorenone-Fused Coumarins

Dedicated to Professor Adrian Schwan of the University of Guelph on the occasion of his 60^th birthday

Abstract

The base-catalyzed reaction of diethyl 1,3-acetonedicarboxylate with 2-hydroxybenzylidene indenediones was studied. The reaction provides a facile and expeditious protocol for the synthesis of natural product inspired fluorenone-fused coumarins in good to very good yields. This process resembles a combination of domino Michael–intramolecular Knoevenagel–aromatization–lactonization reactions in a single step. Although this reaction operates with many bases, the best yields were obtained with DMAP as a catalyst. This protocol could open new potential avenues for the synthesis of fused coumarins by the reaction of substituted β-keto esters with different 2-(2-hydroxybenzylidenes) of 1,3-dicarbonyl compounds.

Key words

coumarin - fluorenone - indandione - DMAP - benzo[c]chromen-6-ones

Polycyclic organic motifs are abundant in synthetic and naturally occurring molecules that exhibit a diverse spectrum of applications.[1] However, the complexity and diversity in their structures bring challenges to synthetic organic chemists. Therefore, the discovery and development of efficient synthetic routes to polycyclic scaffolds have been a pivotal research target.[2] [3] [4]

Coumarin is a privileged scaffold that is omnipresent in natural products, pharmaceuticals, and organic materials. Coumarins fused to polycyclic systems have received substantial interest from organic,[5] [6] [7] [8] [9] medicinal,[10–14] and material chemists for their unique photophysical and photochemical properties.[15–19]

Fluorenone (Figure [1]) is an example of a polycyclic framework that is widespread in natural products.[20] For instance, the natural products Gramniphenols D and E (Figure [1]) exhibit anti-HIV activity.[21] In addition, Caulophine (Figure [1]) displays antimyocardial ischemia activity.[22] Substituted fluorenones are also abundantly present in bioactive organic molecules[23] and photoelectric materials.[24] [25] As a result, there has been a growing interest in the synthesis of substituted fluorenones.[26,27]

Figure 1 Fluorenone and natural products containing fluorenone

Considering the importance of both coumarin and fluorenone, it is anticipated that molecules combining both nuclei would find applications in various fields. However, the synthesis of compounds containing fluorenone fused to coumarin has been rarely studied. Tanaka and coworkers reported the synthesis of molecules containing a fluorenone-fused coumarin core by employing transition-metal catalyst, ligand, and multistep synthesis of starting materials.[28]

The base-mediated reactions of diethyl 1,3-acetonedicarboxylate with 2-hydroxychalcones have been employed in the synthesis of benzene fused coumarins (Scheme [1]).[29] [30] [31]

Scheme 1 Reactions of diethyl 1,3-acetonedicarboxylate with 2-hydroxychalcones

However, the reaction of substituted β-keto esters with 2-(2-hydroxybenzylidene) of both cyclic and acyclic 1,3-dicarbonyl compounds have never been studied. This type of reactions could provide a template for the synthesis of a wide variety of new fused coumarins.

In view of the importance of coumarin and fluorenone entities and in continuation of our efforts in the synthesis of fused coumarins,[32] [33] we report herein the base-catalyzed reaction of diethyl 1,3-acetonedicarboxylate with 2-hydroxybenzylideneindenediones leading to fluorenone-fused coumarins.

Our study commenced with the preparation of the precursors 2-hydroxybenzylideneindenediones 3a–k utilizing the well-established l-proline-catalyzed condensation of 1,3-indandione (1) with substituted salicylaldehydes 2a–k (Scheme [2], Table [1]).[34]

Scheme 2 Synthesis of 2-hydroxybenzylideneindenediones 3a–k

Our efforts were then directed toward the investigation of the reaction of diethyl 1,3-acetonedicarboxylate (4) with the synthesized 2-hydroxybenzylideneindenediones 3a–k. The reaction of diethyl 1,3-acetonedicarboxylate (4) with the chalcone 3a was chosen as a model reaction (Table [2]).

Table 1 Salicylaldehydes 2a–k and 2-Hydroxybenzylideneindenediones 3a–k Utilized in this Study

Compd	R1	R2	R3
2a, 3a	H	H	H
2b, 3b	OMe	H	H
2c, 3c	H	H	Cl
2d, 3d	H	H	OMe
2e, 3e	H	H	Br
2f, 3f	I	H	I
2g, 3g	H	H	NO2
2h, 3h	Br	H	Br
2i, 3i	Cl	H	Cl
2j, 3j	F	H	F

In our initial experiment, 2-hydroxybenzylideneindenedione 3a was reacted with diethyl 1,3-acetonedicarboxylate in refluxing ethanol in the presence of catalytic amount (30 mol%) of Cs₂CO₃ (entry 1, Table [2]). After two hours, TLC analysis indicated completion of the reaction. Upon cooling and addition of 10% acetic acid aqueous solution, a solid precipitated. The solid was crystallized from 1,4-dioxane to afford yellowish needles in 39% yield. The spectroscopic analysis of the product supported our proposed structure of resultant fluorenone-fused coumarin 5a.

Table 2 Screening of the Reaction Conditions for the Reaction of Diethyl 1,3-Acetonedicarboxylate 4 with Chalcone 3a ^a

Entry	Catalyst (loading)	Solvent	Yield (%)b
1	Cs2CO3 (30 mol%)	EtOH	39
2	K2CO3 (30 mol%)	EtOH	27
3	MeCO2Na (30 mol%)	EtOH	25
4	piperidine (30 mol%)	EtOH	15
5	Et3N (30 mol%)	EtOH	54
6	l-proline (30 mol%)	EtOH	51
7	DMAP (30 mol%)	EtOH	62
8	DMAP (10 mol%)	EtOH	50
9	DMAP (1 equiv)	EtOH	40
10	–	EtOH	traces
11	DMAP (30 mol%)	EtOH	32c
12	DMAP (30 mol%)	dioxane	52
13	DMAP (30 mol%)	toluene	48
14	DMAP (30 mol%)	MeCN	42

^a Reactions were performed as: chalcone 3a (1 equiv), compound 4 (1.2 equiv) at 70 °C for 2 h.

^b Isolated yield.

^c Reaction was performed at room temperature. The product formed after overnight stirring.

Motivated by this success, we then directed our efforts toward the optimization of the reaction conditions for better yields (Table [2]). Thus, we tested the catalytic effect of K₂CO₃ and MeCO₂Na (entries 2 and 3), both bases gave lower yields than Cs₂CO₃. The lowest yield was obtained when piperidine was used as a catalyst (entry 4), presumably due to its nucleophilicity and ability to react with hydroxybenzylideneindenediones.[35] On the other hand, other organic bases such as Et₃N and l-proline improved the reaction yield (entries 5 and 6). The best yield was obtained when 4-dimethylaminopyridine (DMAP) was used to catalyze the reaction[36] (entry 7). Lowering the catalyst loading decreased the reaction yield (entry 8). When a stoichiometric amount of the catalyst was used, the reaction yield decreased (entry 9). The uncatalyzed reaction could also afford the product but with very low yield (entry 10). The desired product needed longer time to form at room temperature and the yield was relatively low (entry 11). The reaction was also successful with nonpolar and polar aprotic solvents (entries 12–14).

Several substituted 2-hydroxybenzylideneindenediones tolerated the optimized reaction conditions and gave the desired corresponding products (Table [3]). Mono- and dihalo-substituted fluorenone-fused coumarins 5c, 5e, 5f, 5h, 5i, and 5j were obtained in good yields. The importance of halogenation originates from a well-established drug discovery hypothesis that addition of halogens to bioactive molecules would induce antagonistic or agonist responses compared to the nonhalogenated versions of those compounds.[37] Moreover, halogen substitution is a key strategy in hit-to-lead or lead optimization strategies in pharmaceutical industry as it enhances various biophysicochemical processes such as membrane binding and permeation.[38] Methoxy-substituted 2-hydroxybenzylideneindenediones also tolerated the optimized reaction conditions and yielded 5b and 5d with 46% and 60% yields, respectively. In addition to that, 2-hydroxybenzylideneindenedione derived from 5-nitrosalicylaldehyde gave the corresponding nitro-substituted fluorenone-fused coumarin 5g in very good yield. Although the crude NMR spectrum indicated that 2,4-dihydroxybenzylideneindenedione managed to yield the desired coumarin 5k, the compound was tedious to purify.

Table 3 Substituent Scope of the Coumarins 5a–k

Compd	R1	R2	R3	Yield (%)a
5a	H	H	H	62
5b	OMe	H	H	46
5c	H	H	Cl	55
5d	H	H	OMe	60
5e	H	H	Br	58
5f	I	H	I	49
5g	H	H	NO2	58
5h	Br	H	Br	50
5i	Cl	H	Cl	53
5j	F	H	F	52
5k	H	OH	H	~30

^a Isolated yields.

Based on our findings and the literature,[30] the reaction presumably proceeds via domino Michael–intramolecular Knoevenagel–aromatization–lactonization reactions. A tentative mechanism is depicted in Scheme [3]. The Michael addition of anion A to the 2-hydroxybenzylideneindenedione 3a leads to the formation of the intermediate B. Subsequent intramolecular Knoevenagel condensation and lactonization results in the formation of intermediate C which upon enolization and oxidation gives the desired fluorenone-fused coumarin 5a.

Scheme 3 A plausible mechanism for the formation of fluorenone-fused coumarins 5a

In summary, we have developed a new facile and expeditious protocol of the synthesis of substituted fluorenone-fused coumarins by the base-catalyzed reaction of diethyl 1,3-acetonedicarboxylate with 2-hydroxybenzylideneindenediones. This reaction represents the first cyclization of diethyl 1,3-acetonedicarboxylate with 2-(2-hydroxybenzylidene) of 1,3-dicarbonyl compounds. The reaction operates with many bases and solvents. However, the optimized conditions required the use of DMAP as a catalyst.

Acknowledgment

We thank Central Laboratories Unit and Environmental Science Center, Qatar University for their support in compounds analysis.

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Publication History

Received: 02 January 2021

Accepted after revision: 07 February 2021

Accepted Manuscript online:
07 February 2021

Article published online:
18 February 2021