Tandem Knoevenagel–Michael reactions in aqueous diethylamine medium: A greener and efficient approach toward bis-dimedone derivatives

1 Introduction

In recent, the development of environmentally benign and clean synthetic procedures has become the most desired goal in the field of organic synthesis. Therefore, organic reactions in green solvents have attracted much attention; especially from the viewpoints of green chemistry (Gawande et al., 2013). Green chemistry approaches can lower energy costs, waste chemicals and reduce byproducts. The possibility of carrying out multi-component reactions under green solvents can improve their ecological value (Anastas and Williamson, 1998). Reactions in aqueous media are environmentally safe, devoid of carcinogenic effects due to other solvents have simple work up, and are especially suited for industry (Grieco, 1998; Akbar and Mohammad, 2010). Thus, there is a need for the development of multicomponent reactions (MCRs) in water, without the use of any harmful organic solvents and catalysts.

Knoevenagel condensation is one of the most significant C–C bond constricting method in organic chemistry (Tietze and Beifuss, 1991; Posner, 1986), that involves the reaction of carbonyl compounds with active methylene group in the presence of amines (Knoevenagel, 1894; Knoevenagel, 1896). Combination of this reaction with other reactions in a Domino manner is termed as multicomponent coupling reaction (MCRs) (Bunce, 1995; Tietze and Rackelmann, 2005; Tietze and Brasche, 2006; Hasaninejad et al., 2013a,b). Moreover, MCRs are attractive choice for organic chemists because of operational simplicity, reduced steps for work-up, extraction, purification, and facile automation and minimal waste generation (Zhu and Bienayme, 2005; Nicolaou et al., 2006).

Dimedone (1) is one of the most important substrates among the active methylene compounds, having 1,3-dicarbonyl groups flanked by active methylene groups, which can exists in trans-enolized tautomer form, stabilized by intermolecular hydrogen bonding network (Mark et al., 2011; Xu et al., 2005). It has been used as a versatile synthetic precursor for the synthesis of several classes heterocyclic and spirocyclic compounds (El Ashry et al., 2009). A number of dimedone derived heterocyclic and non-heterocyclic compounds have been reported in the literature for their biological properties, such as tetrahydrobenzo[b]pyrans (Akbar and Mohammad, 2010), fused spiroketal derivatives (Giasuddin Ahmed et al., 2005), bis-spiropiperidine derivatives (Atar and Jeong, 2013), 5-aminouracil derivatives (Shaker et al., 2009), triazolo[1,2-a]indazole-triones (Nikpassand et al., 2009), fused 1,4-dihydropyridines (Mosaddegh and Hassankhani, 2012), isoquinolines (Ivanov and Nikolova, 2008), spirocarbocycles (Clavier et al., 2012), 9-aryl-1,8-dioxooctahydroxanthene derivatives (Ilangovan, et al., 2012) and others (Al-Majid et al., 2013a,b). Therefore, we employed tandem Knoevenagel–Michael reaction in our ongoing research for the one-pot synthesis of various dimedone derivatives. We report here, diethyl amine catalyzed tandem Knoevenagel–Michael reactions of dimedone with various substituted aromatic aldehyde in aqueous medium as a new, robust, greener and highly efficient procedure for the synthesis of bis-dimedone derivatives.

2 Experimental

3 Results and discussion

In our initial finding, a typical one-pot two-component tandem Knoevenagel–Michael reactions were carried out upon treating a mixture of 5,5-dimethylcyclohexane-1,3-dione (dimedone 1), benzaldehyde 2a in 2:1 molar ratio in the presence of one equivalent diethylamine in aqueous medium (1.5 mL) at room temperature, to afford trimolecular adduct salts 3a (Table 1, entry 1). The product 3a was isolated in its pure form with 95% yield, simply by filtration. The structure of the compound 3a was elucidated by means of spectroscopic data and elemental analyses. The ¹H-NMR spectrum of compound 3a showed the absence of the methylene proton of dimedone moiety and the presence of a set of characteristic protons at δ 5.74 (s), 8.25 (bs) and 13.91 (bs) ppm, belonging to the protons of bridge CH, diethylamine NH₂⁺ and OH, respectively. The formation of compound 3a was further confirmed by ¹³C-NMR spectrum and the characteristic peaks were observed at δ 34.2, 179.3 and 199.1 ppm for the bridged CH, C–OH and C⚌O accordingly.

Table 1 Conditions screening for the tandem Knoevenagel–Michael condensation reaction of 1 with benzaldehyde 2a as model substrate.^a

Entry	Condition	Time (h)	Yield (%) b
1	Et2NH/H2O	0.5	95
2	iPr2NH/H2O	1	81
3	(Cyclohexyl)2NH/H2O	2	86
4	Morpholine/H2O	2	67
5	Et3N/H2O	1	59
6	NaOH/H2O	8	54
7	Et2NH	12	13
8	H2O	12	0

a All reactions were carried out with dimedone 1 (3 mmol), benzaldehyde 2a (1.5 mmol) and amine (1.5 mmol) in water (1.5 mL) for the specified time.

b Yield of isolated product.

By inspiring with the result, we further investigated the effect of different amines and reaction parameters on the tandem Knoevenagel–Michael condensation for the synthesis of bis-dimedone derivatives as depicted in Table 1. Because of the fact that the aqueous diethylamine medium gave the desired product 3a with quantitative yield within 30 min (Table 1, entry 1), several secondary amines were therefore tested as compared to diethylamine for the tandem Knoevenagel–Michael condensation reactions. The product 3a was obtained in moderate to good yields in case of aqueous diisopropylamine (81% yield), dicyclohexylamine (86% yield), and morpholine (67% yield) with lower reaction rates as compared to diethylamine (Table 1, entries 2–4 respectively). Moreover, the reaction was further carried out in the aqueous triethylamine and NaOH medium, and the result was found to be less efficient as compared to the secondary amines, only 54–59% yield was observed (Table 1, entry 5, 6). We also found that in the absence of water (Table 1, entry 6) or with only water as a reactant (Table 1, entry 7), the reaction either could not be processed or preceded very slowly or in very harsh condition.

To illustrate the versatility of tandem Knoevenagel–Michael reactions, a series of aromatic aldehydes 2b–n were examined under the optimized reaction condition and the results are summarized in Table 2.

Table 2 Tandem Knoevenagel–Michael reactions of dimedone 1 with aromatic aldehydes 2b–n in aqueous diethylamine medium.^a

Entry	3	R	Time (min)	Yield (%)b
1	3b	p-CH3Ph	45	93
2	3c	p-ClPh	45	92
3	3d	p-BrPh	45	90
4	3e	m-BrPh	45	88
5	3f	p-CH3OPh	45	89
6	3g	2,4,6-(CH3)3Ph	90	85
7	3h	p-NO2Ph	60	90
8	3i	m-CH3Ph	60	91
9	3j	p-HO-Ph	60	88
10	3k	2,4-Cl2Ph	90	92
11	3l	2,6-Cl2Ph	90	91
12	3m	o-NO2Ph	60	87
13	3n	2-Naphthaldehyde	60	93

a All reactions were carried out with dimedone (3 mmol), aldehydes 2b–n (1.5 mmol) and diethylamine (1.5 mmol) in water (3.0 mL) for the specified time.

b Yield of isolated product.

Several derivatives of aromatic aldehydes with either electron-donating/withdrawing groups at the ortho-, meta- or para-, even sterically hindered ortho-position on the aromatic ring were tolerated and irrespective of nature of the substituted groups, the reaction gave the corresponding bis-dimedone derivatives 3b–n with very good chemical yields (85–93%) (Table 2). In addition, reactions with substrates 2g, 2k and 2l bearing highly bulky group, proceeded smoothly to give products with very good results (85%, 92% and 91% respectively) (Table 2, entries 9, 10 & 11). Based on the above results, this process was then extended to heterocyclic aldehyde, but unfortunately, the chemistry does not worked at all.

3.1

3.1 Proposed reaction mechanism

A probable mechanism for the tandem Knoevenagel–Michael reaction has been proposed in Fig. 1. Initially, the water molecule makes hydrogen bonding with the keto group of compound 1, and there by activate the C⚌O functional group, which makes it easy for the deprotonation of methylene proton by diethylamine leading to form enolate intermediate [ii]. Then the enolate [iii] attacks the nucleophilic center of the carbonyl group of aldehyde, followed by Knoevenagel condensation to form Knoevenagel condensation adduct [iv] by the loss of water molecule. Finally, the second molecule of enolate further attacks the double bond of Knoevenagel product [iv] and subsequently undergoes Michael addition reaction to form the tandem Knoevenagel–Michael product 3a–n and regenerates water and diethylamine (Gruttadauria et al., 2007; Breslow, 2004; Blackmond et al., 2007; Barakat et al., 2013a,b; Barakat et al., 2014).

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Figure 1 A possible mechanistic pathway.

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The final adduct which can exists in trans-enolized tautomer form, stabilized by intermolecular hydrogen bonding network as shown by

Further studies to elucidate the chemical structures for the final adduct have been achieved by X-ray technique (Figs. 2a and 2b, Figs. 3a and 3b). Slow diffusion of diethyl ether in a solution of pure compound 3b,c in dichloromethane at room temperature for 2 days gave its colorless single crystals. A single crystal of 3b,c of dimensions, 0.40 × 0.22 × 0.18 mm and 0.54 × 0.23 × 0.16 mm, respectively was selected for X-ray diffraction analysis. Data were collected on a Bruker APEX-II CCD area diffractometer equipped with graphite monochromatic Mo Kα radiation ( $\lambda$  = 71073 $\AA$ ) at 297 (2) K. Cell refinement and data reduction were done by Bruker SAINT (Bruker, 2000). SHELXS-97 (Sheldrick, 2008), PARST (Nardelli, 1995) and PLATON (Spek, 2009) were used to solve structure and refine structure (Table 3). The final refinement was performed by full-matrix least-squares techniques with anisotropic thermal data for nonhydrogen atoms on F2. All the hydrogen atoms were placed in calculated positions (Tables 4 and 5).

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Figure 2a The ORTEP generated plot of the X-ray structure of compound 3b with displacement ellipsoids drawn at 20% probability level. Dashed line indicates the inter molecular interaction. The hydrogens not involved in intra molecular interactions are omitted for clarity.

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Figure 2b The crystal packing of compound 3b. Dashed line indicates the inter molecular interaction. The hydrogens not involved in inter molecular interactions are omitted for clarity.

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Figure 3a The ORTEP generated plot of the X-ray structure of compound 3c with displacement ellipsoids drawn at 20% probability level. Dashed line indicates the inter molecular interaction. The hydrogens not involved in intra molecular interactions are omitted for clarity.

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Figure 3b The crystal packing of compound 3c. Dashed line indicates the inter molecular interaction. The hydrogens not involved in inter molecular interactions are omitted for clarity.

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Table 3 The crystal and experimental data of compounds 3b,c.

	Compound 3b	Compound 3c
Empirical formula	C28 H41 N O4	C27 H38 ClNO4
Formula weight	455.62	476.03
Temperature (K)	297(2)	297(2)
Mo Kα radiations, λ	0.71073 $\AA$	0.71073 $\AA$
Crystal system	Monoclinic	Monoclinic
Space group	P21/n	P21/n
a	10.2895(9) $\AA$	10.2816(16) $\AA$
b	18.0995(15) $\AA$	18.080(3) $\AA$
c	15.8615(13) $\AA$	15.637(2) $\AA$
β	107.975(2)	107.076(4)°
Volume	2809.8(4) ${\AA }^3$	2778.6(7) ${\AA }^3$
Z	4	4
Calculated density	1.077 mg/m3	1.138 mg/m3
Absorption coefficient	0.071 mm−1	0.167 mm−1
F(000)	992	1024
Crystal shape and color	Colorless, Block	Colorless, Block
Crystal size	0.40 × 0.22 × 0.18 mm	0.54 x 0.23 x 0.16 mm
θ range	1.76 to 25.50°	1.77–25.50°
h/k/l	−12, 12/−21, 21/−18, 18	−11, 12/−21, 21/−18, 18
Reflections collected	16506	16294
Reflections unique	5028	5185
(Rint)	0.0735	0.0703
R1 with I > 2σ(I)	0.0673	0.0643
R2 with I > 2σ(I)	0.1360	0.1548
R1 for all data	0.1591	0. 1404
R2 for all data	0.1785	0.1852
Goodness of fit	0.982	1.001
Max/min ρ e ${\AA }^3$	0.234/−0.203	0.239/−0.244

Table 4 Hydrogen bonding data for compound 3b.

D	H	A	D-H	H...A	D...A	D-H…A
C27	H27B	O3a	0.9700	2.5600	3.394(4)	144.00
N1	H1A	O4	0.8600	1.9600	2.800(4)	164.00
O2	H2C	O3	1.40(4)	1.06(4)	2.463(3)	177(4)

a Symmetry codes: 1/2 − x,−1/2 + y,1/2 − z.

Table 5 Hydrogen bonding data for compound 3c.

D	H	A	D-H	H...A	D...A	D-H…A
N1	H1A	O1a	0.84(4)	2.23(4)	2.817(5)	128(3)
N1	H1A	O4a	0.84(4)	2.13(4)	2.743(4)	130(4)
O2	H1B	O3	1.18(5)	1.29(5)	2.459(4)	168(4)
N1	H1C	O3	1.01(4)	1.79(4)	2.697(4)	147(3)

a Symmetry codes: 1/2 − x, 1/2 + y, 1/2 − z.

4 Conclusion

In summary, an efficient, mild, greener and cost effective one-pot synthesis process has been developed for the multicomponent tandem Knoevenagel–Michael condensation reactions of aromatic aldehydes with dimedone by aqueous diethylamine medium for the synthesis of novel bis-dimedone derivatives 3a–n which could be of biological significance. In addition, to its efficiency and simplicity of the reaction conditions, it provides very good yields of the products without further purification. Due to the several advantageous factors like simple work-up, environmentally friendly, no hazardous, no need for anhydrous condition, simple purification and short reaction time, the present methodology becomes the robust and practically applicable synthetic process. Further studies on expanding the application of this method and the biological evaluation of these bis-dimedone derivatives are in progress.