Retracted Article: One-pot synthesis of Hantzsch dihydropyridines using a highly efficient and stable PdRuNi@GO catalyst

Abstract

Addressed herein, highly monodispersed PdRuNi nanoparticles furnished with graphene oxide (PdRuNi@GO NPs) were prepared as novel, stable, efficient and exceptionally reusable heterogeneous catalysts for 1,4-dihydropyridine synthesis via multicomponent condensation reactions of various aldehydes with dimedone, ammonium acetate and ethyl acetoacetate at 70 °C in DMF with efficient catalytic performance. These synthesized novel materials were characterized by transmission electron microscopy (TEM), high resolution electron microscopy (HRTEM), X-ray diffraction (XRD), and X-ray photoelectron spectroscopy (XPS). This presented one pot catalytic process is described as a new methodology of the Hantzsch synthesis, which can be assessed as quite simple and efficient as well as exceptionally reusable. At the end of the reaction, one of the highest yields and the shortest times were obtained for the model reaction in the presence of novel monodisperse PdRuNi@GO NPs.

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Introduction

The six-membered heterocyclic compounds are very important components in organic chemistry. Recently, chemists have devoted considerable attention to 1,4-dihydropyridine compounds, due to their important roles in medical,^1,2 biological³ and pharmacological activities.⁴ They are also used as key compounds in drugs.^5,6 For instance, 1,4-dihydropyridine is a common feature for various pharmacological activities such as cyclooxygenase-2 inhibitors,³ inhibitors against α-glucosidase,⁷ anti-inflammatory activity,⁸ myorelaxant activity of gastric fundus,⁹ antimicrobial activity,¹⁰ and antihypertensive activity.^11,12 Nifedipine, nicardipine and amlodipine such as dihydropyridine derivatives are also known in pharmacology as calcium channel blockers used in the treatment of hypertension¹³ (Scheme 1).

Scheme 1 Examples of 1,4-dihydropyridine derivatives.

1,4-Dihydropyridine compounds also act as catalysts in different types of organic reactions. For instance, these compounds are used as a H₂ surrogate for hydrogenation of α,β-epoxy ketones,¹⁴ alkenes,¹⁵ enamides,¹⁶ and they are key compounds both in cyclization reactions of 1,6-diynes with ruthenium¹⁷ and in asymmetric aza-pinacol cyclization.¹⁸

Hantzsch dihydropyridine synthesis is a multi-component organic reaction of an aldehyde with α,β-keto ester and nitrogen surrogate such as ammonium acetate¹⁹ (Scheme 2).

Scheme 2 Synthesis of 1,4-dihydropyridines.

In recent years, various catalysts are well established for Hantzsch dihydropyridine formations in the literature such as chitosan nanoparticles,²⁰ Yb(OTf)₃,²¹ Sc(OTf)₃,²² ceric ammonium nitrate (CAN),²³ bismuth nitrate,²⁴ La₂O₃,²⁵ Zn-VCO₃ hydrotalcite,²⁶ sodium perchlorate,²⁷ Triton X-100,²⁸ samarium chloride,²⁹ Zr(H₂PO₄)₂,³⁰ ASA (alumina sulfuric acid)³¹ and PtNPs@GO.³² Presently, heterogeneous catalysts are particularly attractive because of the minimum amount of catalyst used, reusability, recoverability and tolerable metal leaching to the solution.³³

Herein, a novel monodispersed heterogeneous catalyst, PdRuNi@GO NPs, was used for dihydropyridine formation. The reaction was carried out with mild conditions and product yields were quite high (Scheme 3).

Scheme 3 PdRuNi@GO NPs assisted 1,4-dihydropyridine synthesis.

Results and discussion

Graphene oxide (GO) (Fig. S1–S4†) and monodisperse PdRuNi@GO NPs were characterized using XRD, TEM, HRTEM and XPS techniques. For example, Fig. 1 shows the XRD pattern of PdRuNi@GO NPs, which shows a similar diffraction pattern to that of Pd@GO, but with a slight shift to higher 2θ values due to alloy formation. The diffraction pattern at around 2θ = 40.20°, 46.72°, and 68.36° can be related to (111), (200) and (220) planes of Pd (JCPDS card numbers 87-0637 of Pd). The diffraction peak at around 2θ = 25.5° corresponds to the characteristic hexagonal structure of graphene oxide. The inset in Fig. 1 represents the extended (111) and (200) peaks showing a slight shift in peak position, and there is no evidence of any peaks relating to metal oxides. The average crystallite size of PdRuNi@GO NPs was calculated from the related XRD patterns using the Scherrer equation and it was found to be a 3.64 nm crystalline particle size.^34–41

Fig. 1 XRD pattern of PdRuNi@GO NPs.

Particle size distribution and bulk structure were portrayed by TEM and HR-TEM, which are shown in Fig. 2. The TEM image of PdRuNi@GO (Fig. 2a) demonstrates that fine particles were homogeneously distributed onto the graphene oxide support. Moreover, the HR-TEM image for monodisperse PdRuNi@GO was additionally used to analyse the atomic lattice fringes in Fig. 2b. As an effect of these edges, Pd (111) planes were seen with 0.22 nm separation of the prepared catalyst, which is exactly the same as nominal Pd (111) dividing of 0.22 nm, respectively.⁴² A particle size histogram was performed for a distribution test of 100 particles and then it was shown that the distribution was Gaussian and the most plausible size of the particles was around 3.72 ± 0.41 nm (Fig. 2c). Particle size from the TEM results agreed well with the XRD results. As induced from ICP-OES, the atomic composition of PdRuNi@GO in aqua regia solution was 70 : 20 : 10, individually which agreed well with those by EDX investigation.

Fig. 2 (a) TEM, (b) HR-TEM image and (c) particle size histogram of PdRuNi@GO NPs.

XPS investigations were performed to analyse the electronic structure and surface organization of PdRuNi@GO. Fig. 3a–c demonstrates the Pd(3d), Ru(3p) and Ni(2p) XPS spectra of PdRuNi@GO NPs. The Pd3d region consists of two spin–orbit part peaks of Pd3d_5/2 and Pd3d_3/2 states.⁴³ Every peak was deconvoluted with various Pd oxidation conditions of metallic Pd(0) and PdO(+2) (Fig. 3a). The ratios of the metallic state and oxidized Pd species were ascertained on the premise of the coordination of their individual parts. It was found that the ratio of metallic Pd species to the oxidized Pd species was found to be 2.1. Furthermore, as shown in Fig. 3b, the Ru(3p) XPS range of PdRuNi@GO NPs was investigated rather than Ru(3d) due to the overlapping peaks between C(1s) and Ru(3d). For the situation of the Ru3p state, two recognizable peaks of various intensities at 463.1 and 483.2 eV are likely ascribed to Ru–C and RuO₂·xH₂O, respectively.^44–48 Another two recognizable peaks of Ni(2p) spectra (2p_1/2, 2p_3/2) are situated at binding energies of 855.3 and 873.3 eV, respectively, which are directly related to Ni(0) and Ni(II), as shown in Fig. 3c. The noise in the Ni2p spectra is relatively high due to the low nickel content in the catalysts; however, the signal strength is still sufficient enough to provide effective information.

Fig. 3 (a) Pd3d, (b) Ru3p, (c) Ni2p XPS spectra of PdRuNi@GO nanoparticles.

Adsorption–desorption N₂ experiments were carried out, and the BET method was used for calculating the specific surface area, which was found to be 136.2 m² g⁻¹. The comparison of 1,4-dihydropyridine formation was examined with previously published works. PdRuNi@GO assisted 1,4-dihydropyridine formation was accomplished with high yields. In addition, the reaction was performed in a short time with respect to the previous works, as seen Table 1. Moreover, PdRuNi@GO was a monodispersed heterogeneous catalyst; therefore, it could be successfully reused more than five times with the same strong effect.

Table 1 Comparisons of catalytic efficiency for 1,4-dihydropyridine formation

Catalyst	Reaction conditions	Time	Yield
None^19	Ammonium acetate (2 mmol), ethyl acetoacetate (2 mmol), benzaldehyde (1 mmol), EtOH (5 ml), 70 °C	5 h	50
ASA^30	Ammonium acetate (4.5 mmol), ethyl acetoacetate (6 mmol), benzaldehyde (3 mmol), catalyst (0.6 mmol), water (2 ml), 70 °C	5 h	87
NaOCl3 (ref. 27)	Ammonium acetate (1.5 mmol), ethyl acetoacetate (2 mmol), benzaldehyde (10 mmol), catalyst (10 mmol%), AcCN (10 ml), 70 °C	3 h	89
Yb(OTf)3 (ref. 21)	Ammonium acetate (2 mmol), dimedone (2 mmol), ethyl acetoacetate (2 mmol), benzaldehyde (2 mmol), catalyst (5 mmol%), EtOH (5 ml), RT	5 h	90
Sc(OTf)3 (ref. 22)	Ammonium acetate (1 mmol), dimedone (1 mmol), ethyl acetoacetate (1 mmol), benzaldehyde (1 mmol), catalyst (5 mmol%), EtOH (5 ml), RT	4 h	93
SmCl3 (ref. 29)	Ammonium acetate (2.2 mmol), ethyl acetoacetate (4.4 mmol), benzaldehyde (2 mmol), catalyst (0.2 mmol), AcCN (10 ml), 70 °C	3 h	85
PdNiRu@GO	Ammonium acetate (2 mmol), ethyl acetoacetate (1 mmol), dimedone (1 mmol), benzaldehyde (1 mmol), catalyst (6 mg), DMF (2 ml), 70 °C	45 min	88
	Ammonium acetate (2 mmol), ethyl acetoacetate (2 mmol), benzaldehyde (1 mmol), catalyst (6 mg), DMF (2 ml), 70 °C	45 min	93

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In the present study, the optimization process dealt with adjusting the amount of catalyst, type of solvent system and ambient temperature. DMF was chosen as the solvent because it facilitates reactions that follow polar mechanisms such as nucleophilic reactions. The present synthesis is a nucleophilic reaction with an aldehyde carbonyl carbon. DMF's boiling point is in the range of 152–154 °C.⁴⁹ Next, the effect of temperature was studied. The reaction was not completed when kept for 1 day at room temperature. Even when elevated temperatures up to 50 °C were applied, some reactant was still observed in its original form (70% conversion). 1,4-Dihydropyridine derivative was successfully obtained with around 90% yield when the reaction was carried out at 70 °C for only 45 min using a PdNiRu@GO catalyst (Table 2).

Table 2 The effect of temperature for 1,4-dihydropyridine formation^a

a Reaction conditions: ammonium acetate (2 mmol), ethyl acetoacetate (1 mmol), dimedone (1 mmol), 4-nitrobenzaldehyde (1 mmol) and 6 mg PdRuNi@GO catalyst (9.3 wt% metal content) were added in 2 ml DMF.

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As a result, the reaction condition was well established by using 6 mg of corresponding catalyst, 2 ml of DMF for 45 minutes at 70 °C (Table 3).

Table 3 The result of Hantzsch dihydropyridine synthesis using PdNiRu@GO catalyst^a

Entry	Substrate	Product	TON/TOF (h^−1)	Yield^b (%)	Entry	Substrate	Product	TON/TOF (h^−1)	Yield^b (%)
a Reaction conditions: ammonium acetate (2 mmol), ethyl acetoacetate (2 mmol) or ethyl acetoacetate (1 mmol), dimedone (1 mmol), aldehyde (1 mmol) and 6 mg PdRuNi@GO NPs (9.3 wt% metal content) were added in 2 ml DMF for 45 minutes at 70 °C.b Isolated yield determined by ^1H NMR. All characterizations are given in the ESI.
1			153.1/204.1	88	10			160.1/213.4	92
2			149.6/199.5	86	11			163.5/218.1	94
3			160.1/213.4	92	12			165.3/220.4	95
4			158.3/211.1	91	13			161.8/215.7	93
5			158.3/211.1	91	14			156.6/208.8	90
6			156.6/208.8	90	15			153.1/204.1	88
7			161.8/215.7	93	16			154.8/206.4	89
8			160.1/213.4	92	17			161.8/215.7	93
9			167.0/222.7	96	18			158.3/211.1	91

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The reaction performance was also monitored by different amounts of PdRuNi@GO catalyst. 6 mg of catalyst was sufficient when 1 mmol of reactants wad used, as seen in Table 4.

Table 4 The efficiency of catalytic amount over 1,4-dihydropyridine formation^a

a Reaction conditions: ammonium acetate (2 mmol), ethyl acetoacetate (1 mmol), dimedone (1 mmol), 4-nitrobenzaldehyde (1 mmol) and 6 mg PdRuNi@GO catalyst were added in 2 ml DMF for 45 minutes at 70 °C.

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According to a plausible mechanism, PdRuNi@GO NPs provide more positive carbonyl dimedone groups, as illustrated in Scheme 4. Therefore, elimination of the methylenic proton adjacent to the carbonyl groups becomes easier, which affords easy and fast nucleophilic addition to the aldehyde carbonyl carbon.

Scheme 4 Suggested mechanistic pathway of 1,4-dihydropyridine synthesis.

Reuse of the heterogeneous catalyst was tested and the results are shown in Table 5. After completion of the reaction, PdRuNi@GO was easily separated from the reaction medium by a centrifuge followed by washing with methanol and water and then dried under vacuum before reuse. As a consequence, PdRuNi@GO catalyst was able to be reused more than five times without any decreased catalytic function. Palladium, ruthenium and nickel content were determined by ICO-OES analysis to be approximately 0.6 ppm in the solution after being reused five times. Furthermore, SEM images and EDX patterns for PdRuNi@GO were analyzed before and after the 5th usage, as shown in Fig. S5 and S6,† and it was observed that there is not much change in the metal content of PdRuNi@GO, as shown in the EDX spectra.

Table 5 Reusability analysis for PdRuNi@GO NPs^a

a Reaction conditions: ammonium acetate (2 mmol), ethyl acetoacetate (2 mmol), benzaldehyde (1 mmol) and 6 mg PdRuNi@GO catalyst in 2 ml DMF for 45 minutes at 70 °C.

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Conclusions

In conclusion, traditional 1,4-dihydropyridine synthetic methods have several disadvantages such as long reaction time, tedious work-up procedure, low yield, and difficult refluxing conditions. However, the novel monodisperse PdRuNi@GO NPs provided one of the highest yields and the shortest time as a novel, stable, long-lived, efficient and exceptional reusable heterogeneous catalyst for 1,4-dihydropyridine synthesis via multicomponent condensation reactions of various aldehydes with dimedone, ammonium acetate and ethyl acetoacetate at 70 °C in DMF with efficient catalytic performance. The current catalytic process was described as an easy, effective, practical and exceptional reusable synthetic method for Hantzsch synthesis. This nano sized heterogeneous catalyst showed excellent catalytic activity for a model reaction with mild conditions and this was most likely due to high monodispersity, low crystalline particle size and a high percentage of metal(0) contents in the prepared PdRuNi@GO NPs. Since the given methodology is efficient and practical, this method would be a rather attractive synthetic method in the near future.

Experimental

Preparation of monodisperse Pd–Ni–Ru@GO NPs

Monodisperse PdRuNi@GO NPs were prepared using the sonochemical double solvent reduction method. Summarizing this process, superhydride and ethanol were used to reduce a 0.25 mmol mixture of precursors Pd, Ni and Ru lysed in a small amount of dehydrated tetrahydrofuran and 0.25 mmol of octanethiol (OT) ligand under ultrasonic conditions. A brown-black color solution indicated the formation of PdRuNi NPs.^39–41 Finally, at room temperature, the solid Pd–Ni–Ru NPs were dried under vacuum. The prepared PdNiRu NPs were mixed in a 1 : 1 (mole) ratio with GO using a probe sonicator to obtain the PdRuNi@GO NPs. The ultrasonication method was employed to increase the PdRuNi@GO NPs dispersion on GO. The data showed that the route is very effective for a making uniform distribution of PdRuNi@GO NPs on GO and for mitigating agglomeration problems with NPs.

General procedure of 1,4-dihydropyridine synthesis

Ammonium acetate (2 mmol), ethyl acetoacetate (2 mmol), aldehyde (1 mmol) and 6 mg PdRuNi@GO catalyst were added to 2 ml DMF. The reaction was kept at 70 °C for 45 min. After completion of the reaction, the catalyst was removed by centrifugation (6000 rpm) and PdRuNi@GO catalyst was washed with methanol and water and then dried. DMF solution was poured into 20 ml of ice-cold water. The resulting precipitate was filtered and the solid was allowed to dry.

Diethyl-2,6-dimethyl-4-phenyl-1,4-dihydropyridine-3,5-dicarboxylate (1)³¹. ¹H NMR (CDCl₃, 300 MHz): δ 1.22 (6H, t, J = 7.05 Hz, –CH₃), 2.31 (6H, s, –CH₃), 4.09 (4H, q, J = 6.80 Hz, –OCH₂), 4.99 (1H, s, –CH), 5.81 (NH, s), 7.14–7.25 (5H, m, Ar-H). ¹³C NMR (CDCl₃, 75 MHz): δ 14.52, 19.81, 39.84, 60.02, 104.12, 126.31, 128.06, 128.21, 144.45, 148.02, 168.09.

Diethyl-4-(4-bromophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (2)³¹. ¹H NMR (CDCl₃, 300 MHz): δ 1.22 (6H, t, J = 7.10 Hz, –CH₃), 2.33 (6H, s, –CH₃), 4.06 (4H, q, J = 6.70 Hz, –OCH₂), 4.95 (1H, s, –CH), 5.61 (NH, s), 7.16 (2H, d, J = 8.80 Hz, Ar-H), 7.26 (2H, d, J = 8.80 Hz, Ar-H). ¹³C NMR (CDCl₃, 75 MHz): δ 14.5, 19.9, 39.5, 60.0, 104.0, 120.11, 130.0, 131.11, 144.1, 147.0, 167.6.

Diethyl-2,6-dimethyl-4-(4-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate (3)³¹. ¹H NMR (CDCl₃, 300 MHz): δ 1.27 (6H, t, J = 7.20 Hz, –CH₃), 2.37 (6H, s, –CH₃), 4.21 (4H, q, J = 6.70 Hz, –OCH₂), 5.31 (1H, s, –CH), 6.05 (NH, s), 7.43 (2H, d, J = 9.01 Hz, Ar-H), 8.09 (2H, d, J = 9.01 Hz, Ar-H). ¹³C NMR (CDCl₃, 75 MHz): δ 20.81, 30.77, 39.83, 113.48, 124.04, 128.72, 144.17, 146.88, 153.32, 197.27.

Diethyl-4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (4). ¹H NMR (CDCl₃, 300 MHz): δ 1.10 (6H, t, J = 7.20 Hz, –CH₃), 2.25 (6H, s, –CH₃), 4.07 (4H, q, J = 6.75 Hz, –OCH₂), 5.06 (1H, s, –CH), 5.80 (1H, NH), 7.08 (1H, t, –CH), 7.11 (2H, d, J = 9.01 Hz, Ar-H), 8.10 (1H, s, Ar-H). ¹³C NMR (CDCl₃, 75 MHz): δ 14.41, 19.87, 40.12, 60.21, 103.65, 121.53, 123.38, 128.81, 134.73, 144.81, 148.32, 150.11, 167.37.

Diethyl-4-(4-cyanophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (5). ¹H NMR (CDCl₃, 300 MHz): δ = 1.17 (6H, t, J = 7.2 Hz, –CH₃), 2.39 (6H, s, –CH₃), 4.05 (4H, q, J = 6.70 Hz, –OCH₂), 5.06 (H, s, –CH), 5.92 (NH, s), 7.43 (2H, d, J = 7.80 Hz, Ar-H), 7.52 (2H, d, J = 7.71 Hz, Ar-H), ¹³C NMR (CDCl₃, 75 MHz): δ 14.12, 50.87, 115.42, 109.71, 111.49, 119.52, 129.17, 132.13, 144.29, 148.64, 152.62, 167.14.

Diethyl-4-(4-(dimethylamino)phenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (6)⁴⁹. ¹H NMR (CDCl₃, 300 MHz): δ 1.26 (6H, t, J = 7.21 Hz, –CH₃), 2.32 (6H, s, –CH₃), 2.90 (6H, s, –CH₃), 4.15 (4H, q, J = 6.70 Hz, –OCH₂), 4.81 (1H, s, –CH), 5.51 (NH, s), 6.70 (2H, d, J = 8.60 Hz, Ar-H), 7.10 (2H, d, J = 8.60 Hz, Ar-H). ¹³C NMR (CDCl₃, 75 MHz): δ 14.23, 21.36, 40.32, 43.21, 62.78, 103.62, 114.25, 129.82, 135.26, 146.73, 150.76, 168.22.

Ethyl-2,7,7-trimethyl-5-oxo-4-phenyl-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate (7)³¹. ¹H NMR (CDCl₃, 300 MHz): δ 0.92 (3H, s, –CH₃), 1.04 (3H, s, –CH₃), 1.21 (3H, t, J = 7.20 Hz, –CH₃), 2.10–2.26 (4H, m, –CH₂), 2.30 (3H, s, –CH₃), 4.06 (2H, q, J = 7.20 Hz, –OCH₂), 4.66 (1H, s, –CH) 5.05 (NH, s), 7.11–7.31 (5H, m, Ar-H). ¹³C NMR (CDCl₃, 75 MHz): δ 14.42, 19.55, 27.33, 29.77, 32.93, 36.88, 41.02, 51.04, 60.03, 106.17, 112.13, 126.22, 128.18, 128.23, 144.08, 147.33, 149.26, 167.73, 196.09.

Ethyl-4-(4-bromophenyl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate (8)³¹. ¹H NMR (CDCl₃, 300 MHz): δ0.91 (3H, s, –CH₃), 1.06 (3H, s, –CH₃), 1.19 (3H, t, J = 7.10 Hz, –CH₃), 2.14–2.32 (4H, m, –CH₂), 2.35 (3H, s, –CH₃), 4.05 (2H, q, J = 7.10 Hz, –OCH₂), 5.00 (1H, s, –CH), 6.58 (NH, s), 7.19 (2H, d, J = 7.60 Hz, Ar-H), 7.30 (2H, d, J = 7.70 Hz, Ar-H). ¹³C NMR (CDCl₃, 75 MHz): δ 14.44, 19.63, 27.35, 29.74, 32.98, 36.54, 41.18, 50.98, 60.14, 105.89, 111.84, 120.09, 130.04, 131.10, 144.14, 146.46, 149.06, 167.54, 195.98.

Ethyl-2,7,7-trimethyl-4-(4-nitrophenyl)-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate (9). ¹H NMR (CDCl₃, 300 MHz): δ 0.90 (3H, s, –CH₃), 1.08 (3H, s, –CH₃), 1.82 (3H, t, J = 7.10 Hz, –CH₃), 2.16–2.36 (4H, m, –CH₂), 2.40 (3H, s, –CH₃), 4.04 (2H, q, J = 7.80 Hz, –OCH₂), 5.15 (1H, s, –CH), 6.31 (NH, s), 7.50 (2H, d, J = 7.80 Hz, Ar-H), 8.09 (2H, d, J = 7.8 Hz, Ar-H). ¹³C NMR (CDCl₃, 75 MHz): δ 14.33, 18.97, 27.03, 29.57, 32.54, 37.29, 50.74, 59.79, 103.47, 110.27, 123.14, 129.03, 145.99, 146.04, 150.294, 155.23, 167.14, 195.47.

Ethyl-2,7,7-trimethyl-5-oxo-4-p-tolyl-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate (10)³¹. ¹H NMR (CDCl₃, 300 MHz): δ 0.94 (3H, s, –CH₃), 1.06 (3H, s, –CH₃), 1.22 (3H, t, J = 6.40 Hz, –CH₃), 2.11–2.21 (4H, m, –CH₂), 2.25 (3H, s, –CH₃), 2.33 (3H, s, –CH₃), 4.07 (2H, q, J = 6.40 Hz, –OCH₂), 5.00 (1H, s, –CH), 6.49 (NH, s), 7.00 (2H, d, J = 7.60 Hz, Ar-H), 7.19 (2H, d, J = 8.0 Hz Ar-H). ¹³C NMR (CDCl₃, 75 MHz): δ 14.51, 19.52, 21.36, 27.43, 29.79, 32.93, 36.39, 41.14, 51.09, 60.04, 106.36, 112.39, 128.13, 128.80, 135.63, 143.82, 144.51, 148.94, 167.87, 195.92.

Ethyl-4-(2,4-dimethoxyphenyl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate (11)³¹. ¹H NMR (CDCl₃, 300 MHz): δ 0.91 (3H, s, –CH₃), 1.03 (3H, s, –CH₃), 1.20 (3H, t, J = 7.20 Hz, –CH₃), 2.06–2.22 (4H, m, –CH₂), 2.27 (3H, s, –CH₃), 3.73 (3H, s, –OCH₃), 3.76 (3H, s, –OCH₃), 3.99–4.06 (2H, q, J = 7.20 Hz, –OCH₂), 5.16 (1H, s, –CH), 6.35 (2H, d, J = 7.20 Hz, Ar-H), 6.52 (NH, s, Ar-H), 7.19 (1H, s, Ar-H). ¹³C NMR (CDCl₃, 75 MHz): δ 14.43, 19.41, 26.92, 29.86, 32.72, 33.26, 41.13, 51.03, 55.47, 55.52, 59.86, 98.53, 104.25, 105.24, 110.93, 127.72, 131.81, 143.43, 149.35, 158.62, 159.27, 168.32, 195.87.

Ethyl-4-(4-cyanophenyl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate (12). ¹H NMR (CDCl₃, 300 MHz): δ 0.90 (3H, s, –CH₃), 1.08 (3H, s, –CH₃), 1.17 (3H, t, J = 7.20 Hz, –CH₃), 2.18 (2H, s, –CH₂), 2.23 (2H, s, –CH₂), 2.39 (3H, s, –CH₃), 4.05 (2H, q, J = 7.20 Hz, –OCH₂), 5.09 (H, s, –CH), 6.22 (NH, s), 7.42 (2H, d, J = 7.80 Hz, Ar-H), 7.51 (2H, d, J = 7.8 Hz, Ar-H), ¹³C NMR (CDCl₃, 75 MHz): δ 14.11, 19.72, 27.37, 29.52, 32.94, 37.42, 41.25, 50.72, 100.29, 115.14, 109.86, 111.42, 119.55, 129.12, 132.11, 144.21, 148.63, 152.52, 167.01, 195.92.

Ethyl-4-(4-(dimethylamino)phenyl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate (13)²². ¹H NMR (CDCl₃, 300 MHz): δ 0.98 (3H, s, –CH₃), 1.09 (3H, s, –CH₃), 1.24 (3H, t, J = 7.20 Hz, –CH₃), 2.29–2.36 (4H, m, –CH₂), 2.88 (6H, s, –NCH₃), 4.09 (2H, q, J = 7.20 Hz, –OCH₂), 4.96 (1H, s, –CH), 5.88 (NH, s), 6.62 (2H, d, J = 7.60 Hz, Ar-H), 7.16 (2H, d, J = 7.60 Hz, Ar-H). ¹³C NMR (CDCl₃, 75 MHz): δ 14.62, 20.11, 27.95, 33.21, 41.36, 41.62, 42.81, 52.42, 63.25, 110.91, 11.35, 129.21, 135.68, 147.83, 148.25, 150.92, 168.18, 192.02.

Ethyl-2,7,7-trimethyl-4-(2-nitrophenyl)-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate (14)⁵⁰. ¹H NMR (CDCl₃, 300 MHz): δ 0.88 (3H, s, –CH₃), 0.96 (3H, t, J = 7.20 Hz, –CH₃), 1.01 (3H, s, –CH₃), 2.14–2.20 (4H, m, –CH₂), 2.31 (3H, s, –CH₃), 3.99 (2H, m, –OCH₂), 5.64 (1H, s, CH), 6.66 (NH, s), 7.66–7.32 (4H, m, Ar-H). ¹³C NMR (CDCl₃, 75 MHz): δ 195.14, 167.90, 151.98, 147.91, 146.25, 140.94, 133.53, 130.99, 127.56, 124.90, 111.01, 105.69, 58.95, 51.05, 32.89, 32.63, 29.99, 26.12, 19.25, 14.83.

Ethyl-4-cyclohexyl-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate (15). ¹H NMR (CDCl₃, 300 MHz): δ 0.80 (2H, m, –CH₂), 1.08 (3H, s, –CH₃), 1.10 (3H, s, –CH₃), 1.10–1.12 (4H, m, –CH₂), 1.18 (3H, t, J = 7.10 Hz, –CH₃), 1.61–1.42 (5H, m), 2.19 (3H, s, –CH₃), 2.15–2.55 (4H, m, CH₂), 3.90 (1H, d, J = 4.60 Hz, –CH), 4.10 (2H, m, –OCH₂), 5.88 (NH, s). ¹³C NMR (CDCl₃, 75 MHz): δ 196.42, 170.83, 151.78, 145.96, 109.23, 100.99, 60.25, 51.17, 47.99, 32.57, 30.09, 29.25, 27.78, 25.99, 25.72, 19.57, 14.58.

Ethyl-2,7,7-trimethyl-5-oxo-4-pentyl-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate (16)⁵³. ¹H NMR (CDCl₃, 300 MHz): δ 0.88 (3H, t, J = 6.60 Hz, –CH₃), 0.99 (3H, s, –CH₃), 1.04 (3H, s, –CH₃), 1.19–1.15 (11H, m, –CH/–CH₂), 2.32 (3H, s, –CH₃), 2.54 (4H, m, –OCH₂), 6.88 (NH, s). ¹³C NMR (CDCl₃, 75 MHz): δ 195.20, 168.00, 151.02, 148.30, 108.36, 103.22, 59.99, 51.23, 36.55, 31.04, 30.03, 29.18, 29.16, 26.38, 23.56, 22.15, 18.99, 13.88, 13.65.

Ethyl-2,7,7-trimethyl-4-(naphthalen-2-yl)-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate (17)⁵¹. ¹H NMR (CDCl₃, 300 MHz): δ 0.88 (3H, s, –CH₃), 0.92 (3H, t, J = 7.10 Hz, –CH₃), 0.99 (3H, s, –CH₃), 2.14 (4H, m, –CH₂), 2.31 (3H, s, –CH₃), 4.06 (2H, m, –OCH₂), 5.02 (1H, s, CH), 6.86 (NH, s), 7.90–7.22 (6H, m, Ar-H), 8.68 (1H, m, Ar-H). ¹³C NMR (CDCl₃, 75 MHz): δ 195.38, 167.56, 150.05, 148.21, 143.99, 134.12, 130.93, 127.61, 126.56, 126.47, 126.26, 126.11, 125.58, 125.32, 112.09, 106.99, 60.24, 50.87, 32.85, 31.12, 28.25, 27.08, 18.97, 14.53.

Ethyl-4-(furan-2-yl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate (18)⁵². ¹H NMR (CDCl₃, 300 MHz): δ 0.92 (3H, s, –CH₃), 0.99 (3H, s, –CH₃), 1.11 (3H, t, J = 6.90 Hz), 2.18–2.10 (2H, m, –CH₂), 2.24 (3H, s, –CH₃), 2.40–2.28 (2H, m, –CH₂), 4.08 (2H, t, J = 6.40 Hz, –OCH₂), 5.00 (1H, s), 5.77 (NH, s), 5.90 (1H, s), 6.20 (1H, s, Ar-H), 7.28 (1H, s, Ar-H), 9.13 (1H, s, Ar-H). ¹³C NMR (CDCl₃, 75 MHz): δ 192.61, 168.32, 159.24, 151.25, 146.87, 140.99, 110.46, 107.57, 103.99, 101.86, 61.64, 51.73, 30.99, 30.86, 29.24, 26.23, 19.86, 16.72.

Acknowledgements

This research was supported by the Dumlupinar (2014-05, 2015-35 and 2015-50) and the Duzce University Research Fund (Grant no. 2016.05.03.410). The partial supports by Science Academy and FABED are gratefully acknowledged.

Notes and references

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Footnotes

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c6ra13142e

‡ These authors contributed equally to this work.

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