Synthesis of fused tetrahydropyrido[2,3-c]coumarin derivatives as potential inhibitors for dopamine d3 receptors, catalyzed by hydrated ferric sulfate

Abstract

Fused furo- and pyrano-tetrahydropyrido[2,3-c]coumarin derivatives were synthesized using one-pot three component reactions between aromatic aldehydes, 3-aminocoumarins and cyclic enol ethers in the presence of 10 mol% hydrated ferric sulphate [Fe₂(SO₄)₃·xH₂O] in refluxing acetonitrile. The salient features of the present protocol are good yields, high diastereoselectivities, application to a wide range of substrates, using an inexpensive, readily available and recyclable catalyst and environmentally benign reaction conditions.

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Introduction

Heterocycles are widely distributed in nature and many of them exhibit interesting pharmacological activities.¹ With increasing economic and ecological pressure, new concepts and synthetic strategies are continuously being evolved for the synthesis of valuable organic compounds in a more efficient, cheaper and environmentally benign manner.² Multicomponent reactions³ (MCRs) have been used very successfully to address these issues and now occupy a central position in synthetic organic methodology.⁴ Coumarin as well as their derivatives may be regarded as “privileged structures” in the pharmaceutical and agrochemical industries.⁵ Some of their derivatives are found to possess a wide range of biological activity such as antidepressant,⁶ antitumor,⁷ and anti-inflammatory.⁸ Moreover, fused 3,4-coumarin derivatives⁹ have been used for DNA cleavage¹⁰ and also act as antagonists of platelet activating factor.¹¹ Therefore, the synthesis of fused 3,4-coumarin compounds containing a tetrahydropyridine moiety is highly desirable.

The aza-Diels–Alder reaction is a subclass of the hetero-Diels–Alder reaction, amongst which the Povarov reaction¹² is one of the most important approaches for the construction of tetrahydroquinolines from N-arylimine and cyclic enol ethers¹³ with high stereo-, chemo- and regio-selectivities. As a result, tremendous efforts have been made in the development of aza-Diels–Alder reaction to rapidly synthesise complex enantioenriched bioactive aza-heterocycles and valuable intermediates for the total synthesis of natural products.¹⁴ Conventionally, Povarov reactions are usually carried out using a Lewis acid such as BF₃·OEt₂,¹⁵ lanthanide chloride^13b,16 or scandium triflate.¹⁷ Very recently, we have demonstrated the synthesis of fused heterocycles containing the 3-aminocoumarin skeleton through multicomponent reactions (MCRs).¹⁸ These successful results encouraged us to investigate whether the Povarov reaction can be exploited further for the synthesis of tetrahydropyrido[2,3-c]coumarins using 3-aminocoumarins but involving a less expensive catalyst. A few years ago, Bodwell et al. demonstrated the synthesis of tetrahydropyrido[2,3-c]coumarin derivatives from 3-aminocoumarins, aromatic aldehydes having solely electron-withdrawing substituents in the aromatic ring and cyclic or acyclic enol ethers using Yb(OTf)₃ as catalyst.¹⁹ Although this method is quite useful, it has some limitations such as low yields when it was carried out in a one-pot manner, requirement of expensive and non-reusable catalyst and a lack of substrates variability. Recently, we have reported the usefulness of hydrated ferric sulfate [Fe₂(SO₄)₃·xH₂O] as an efficient heterogenous catalyst for Povarov reactions²⁰ for the synthesis of tetrahydroquinoline derivatives using three-component reactions from aromatic amines, aromatic aldehydes and cyclic enol ethers. Ferric sulfate [Fe₂(SO₄)₃·xH₂O] is a mild, inexpensive and readily available catalyst for various organic transformations such as tetrahydropyranylation of alcohols,^21a preparation of acylals from aldehydes,^21b 2,3-unsaturated glycosides via Ferrier rearrangement,^21c per-O-acetylation of sugars^21d and the synthesis of pyrazole.^21e The unique solubility of the catalyst in acetonitrile/ethanol and insolubility in DCM enables its uses as both homogenous and heterogenous catalyst; it is also easily recovered at the end of reactions by adding DCM. In this paper, we would like to disclose our successful results for the one-pot synthesis of tetrahydropyrido[2,3-c]coumarin derivatives from 3-aminocoumarins, aromatic aldehydes and cyclic enol ethers as shown in Scheme 1 as well as the diastereoselectivity of the adducts.

Scheme 1 One-pot synthesis of tetrahydropyrido[2,3-c]coumarins derivatives.

Results and discussion

Various 3-aminocoumarins were synthesized from 3-acetamidocoumarins, which were prepared by controlled regioselective acid hydrolysis.²² For the present study, a mixture of 4-chlorobenzaldehyde (1 mmol), 3-aminocoumarin (1 mmol) and 3,4-dihydropyran (DHP) (1.1 mmol) in acetonitrile (4 mL) was refluxed in a pre-heated oil-bath in presence of 5 mol% of hydrated Fe₂(SO₄)₃·xH₂O and the diastereomeric products, tetrahydropyrido[2,3-c]coumarins 4c and 5c, were isolated in 66% overall yield with an endo–exo and endo–endo diastereoselectivity of 80 : 20. The diastereomeric ratio was determined from ¹H NMR spectra of the crude reaction mixture and they were also characterized after purification by ¹H NMR, ¹³C NMR spectra and elemental analysis.

For optimizing reaction conditions, various reactions were examined using a combination of 3-aminocoumarin, 4-chlorobenzaldehyde and 3,4-dihydropyran with different amounts of catalyst and different solvents (entries 1–6, Table 1). It was noted that 10 mol% of the hydrated ferric sulfate provided the best result for the formation of products in terms of both yield and reaction time (entry 2, Table 1). It has also been observed that acetonitrile is the best solvent for the present reaction as compared to other solvents such as ethanol, DMF and water. Other catalysts such as p-TSA, In(OTf)₃, CAN and SiO₂ were also scrutinized in acetonitrile under reflux conditions (entries 7–10, Table 1). These catalysts provided either lower yields and required longer reaction times or the reactions were unsuccessful (entries 7–10, Table 1). The reaction did not take place in the absence of catalyst (entry 11, Table 1). After optimizing the reaction conditions, the mixture of 3-aminocoumarin, benzaldehyde and 3,4-dihydropyran in acetonitrile was refluxed using 10 mol% Fe₂(SO₄)₃·xH₂O under identical reaction conditions and the desired tetrahydropyrido[2,3-c]coumarin derivatives 4a and 5a were isolated in 81% combined yield with (81 : 19) endo–exo : endo–endo selectivity (entry a, Table 2).

Table 1 Optimization of reaction conditions for the synthesis of tetrahydropyrido[2,3-c]coumarins 4c and 5c

Entry	Catalyst (mol%)	Solvent	Time/h	Ratio^a 4c : 5c	Yield^b (%)
a The product ratio was determined from ^1H NMR spectra.b Isolated yields. NR = no reaction. A = hydrated ferric sulfate [Fe2(SO4)3·xH2O].
1	A (05)	MeCN	3.0	80 : 20	66
2	A (10)	MeCN	2.5	84 : 16	87
3	A (15)	MeCN	2.5	76 : 24	82
4	A (10)	EtOH	3.0	81 : 19	61
5	A (10)	DMF	12.0	83 : 17	56
6	A (10)	H2O	12.0	71 : 29	48
7	p-TSA (10)	MeCN	12.0	81 : 19	59
8	In(OTf)3 (10)	MeCN	12.0	79 : 21	66
9	CAN (10)	MeCN	12.0	—	NR
10	SiO2 (10)	MeCN	12.0	—	NR
11	None	MeCN	12.0	—	NR

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Table 2 Scope of various substituted tetrahydropyrido[2,3-c]coumarin derivatives^a

Entry	Ar	X	n	Time (h)	Yield^b (%)	Ratio^c (4 : 5)
a The reactions were performed in 1 mmol scale.b Isolated yields.c The product ratio was determined from ^1H NMR spectra of the crude reaction mixture.
a	Ph	H	2	2.0	81	81 : 19
b	4-Me-Ph	H	2	2.0	84	77 : 23
c	4-Cl-Ph	H	2	2.5	87	84 : 16
d	4-Br-Ph	H	2	2.5	86	80 : 20
e	4-F-Ph	H	2	2.5	87	84 : 16
f	4-OMe-Ph	H	2	2.0	87	100 : 00
g	3,4(OMe)2Ph	H	2	2.0	89	100 : 00
h	2-Furfuryl	H	2	2.0	86	100 : 00
i	2-Naphthyl	H	2	2.5	74	84 : 16
j	4-NO2-Ph	H	2	2.0	68	76 : 24
k	Ph	H	1	2.0	85	70 : 30
l	4-Cl-Ph	H	1	2.5	79	71 : 29
m	4-Br-Ph	H	1	2.5	81	68 : 32
n	4-MeO-Ph	H	1	2.5	88	70 : 30
o	2-Furfuryl	H	1	2.0	78	60 : 40
p	4-Cl-Ph	Br	2	2.5	81	75 : 25
q	Furfural	Br	2	2.5	77	78 : 22
r	4-Me-Ph	NO2	2	2.5	78	78 : 22
s	4-Cl-Ph	OMe	2	2.0	82	79 : 21

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Encouraged by these successful results, we have carried out similar reaction with 3-aminocoumarin, 4-methylbenzaldehyde and 3,4-dihydropyran under identical conditions (entry b, Table 2) and the desired products 4b and 5b were obtained in 84% overall yield with a diastereoselectivity of 77 : 23. Likewise, a mixture of 3-aminocoumarin, various aromatic aldehydes having substituents such as Br, F and OMe groups in the aromatic ring as well as 2-furaldehyde and 3,4-dihydropyran were reacted together in the presence of 10 mol% hydrated ferric sulfate under identical reaction conditions. The reaction time, % yield and diastereomeric products ratio i.e. endo–exo : endo–endo ratio are shown in Table 2 (entries a–h). It is noteworthy that we have obtained 100% endo–exo selectivity for the aldehydes 4-methoxybenzaldehyde, 3,4-dimethoxybenzaldehyde and furfurylaldehyde respectively. Furthermore, the reaction was carried out with 3-aminocoumarin (1 mmol), 2-naphthaldehyde (1 mmol) and 3,4-dihydropyran (1.1 mmol) under identical reaction conditions and the desired products were obtained 74% overall yield with diastereoselectivity 84 : 16. We have also performed a reaction of products ratio i.e. endo–exo : endo–endo ratio are shown in Table 2 (entries a–h). It is noteworthy that we have obtained 100% endo–exo selectivity for the aldehydes 4-methoxybenzaldehyde, 3,4-dimethoxybenzaldehyde and furfurylaldehyde respectively. Furthermore, the reaction was carried out with 3-aminocoumarin (1 mmol), 2-naphthaldehyde (1 mmol) and 3,4-dihydropyran (1.1 mmol) under identical reaction conditions and the desired products were obtained 74% overall yield with diastereoselectivity 84 : 16. We have also performed a reaction of 3-aminocoumarin (1 mmol), 4-nitrobenzaldehyde (1 mmol) and 3,4-dihydropyran (1.1 mmol) in presence of 10 mol% hydrated ferric sulfate and isolated the products in 68% overall yield, a distinct improvement on that reported previously (40%).¹⁹ Inspired by all these successful results, we also examined the reactions with other enol ether including 2,3-dihydrofuran with 3-aminocoumarin and a wide variety of aromatic aldehydes using the same amount of catalyst under similar reaction conditions (Table 2, entries k–o). For generalizing the present protocol, we have further verified the reaction with other substituted 3-aminocoumarins and their successful results are included in Table 2 (entries p–s). The reaction was unsuccessful with aliphatic aldehydes under similar reaction condition, which is the only limitation of the present protocol.

Determination of stereochemistry of the reaction products

The stereochemistries of the fused ring junctures and other positions of compounds 4c and 5c were established from their coupling constants from ¹H-NMR spectra. For example, compound 4c (endo–exo isomer), exhibited coupling constants values of J_4a,12c and J_4a,5 are 2.8 Hz and 11.6 Hz, respectively whereas the endo–endo isomer (5c) showed coupling constant values of J_4a,12c and J_4a,5 are 1.6 Hz and 5.2 Hz, respectively, as shown in Fig. 1. The coupling constant values are in full agreement with the earlier reported products.²⁰

Fig. 1 Coupling constant values used for determining stereochemistry.

Moreover, the structure of compounds 4c and 5o were further ascertained through single XRD crystallographic data and their ORTEP diagram is shown in Fig. 2 (see the ESI, Table SI1†). The torsional angle (H-5–C-5–C-4a–H-4a) for the X-ray crystal structure of trans isomer 4c was determined to be 171.47° which is consistent with the observed ³J_4a,5 coupling constants of 11.6 Hz with H-5 and H-4a adopting pseudo-axial positions with an anti relationship. In contrast, the torsional angle (H-5–C-5–C-4a–H-4a) for endo–endo isomer 5o was determined to be 56.41° which is consistent with the observed ³J_3a,4 coupling constants of 7.6 Hz for the compound 5o, characteristic of the syn relationship of these protons in a pseudo-axial–equatorial relationship. These observations are in agreement with the observed ¹H NMR coupling constants of the endo–exo and endo–endo products in the tetrahydroquinoline derivatives previously studied in our group.²⁰

Fig. 2 X-ray crystal structures of (i) 4c and (ii) 5o.†

The formation of tetrahydropyrido[2,3-c]coumarins may be explained as follows: we believe that the condensation reaction between aromatic aldehyde (1) and 3-aminocoumarin (2) leads to the formation of intermediate N-arylimines A (2-azadienes), which undergo a cycloaddition reaction with the electron-rich dienophiles namely 3,4-dihydropyran or 2,3-dihydrofuran in the presence of hydrated ferric sulfate. The dienophile may approach either the endo face or exo-face, as shown in Scheme 2. In the present study, we have found only endo-face selectivity over exo-face selectivity. However, Batey et al.²³ have reported recently exo-face selectivity with N-arylimines, derived from aromatic amines and aromatic aldehydes, and strained norbornene-derived dienophiles.

Scheme 2 Endo selectivity for the formation of tetrahydropyrido[2,3-c]coumarins from the Povarov reaction.

The expected major product would be endo–endo 5a, but we have obtained endo–exo 4a due to steric repulsion between the aryl ring and tetrahydropyranyl ring as shown in Scheme 2. It is also possible that the reactions involve a stepwise mechanism as proposed by Lavilla and his co-workers.^17b

The reusability test of the catalyst was performed as follows: a mixture of benzaldehyde (10 mmol), 3-aminocoumarin (10 mmol), 3,4-DHP (11 mmol, 1 mL) and Fe₂(SO₄)₃·H₂O (1 mmol, 0.410 g) was taken in 30 mL of acetonitrile and it was refluxed for 2 h in a pre-heated oil-bath. After completion of reaction, acetonitrile was recovered in a rotatory evaporator and the crude residue was dissolved in DCM (25 mL). The catalyst separated out as soon as DCM was added. Then, it was filtered off through a Büchner funnel, washed with another 5 mL of DCM and dried. The recovered catalyst was used for a similar set of reactions for three more consecutive cycles. The yields and the number of experiments conducted are shown in the bar diagram in Fig. 3. The tetrahydropyrido[2,3-c]coumarins products are contained in the filtrate, which was concentrated and the residue separated by chromatography to give the pure products. It was observed that the yield decreases in the fourth cycle which may be due to weight loss of the catalyst during handling.

Fig. 3 Reusability of the catalyst.

Next, docking studies of the synthesized 3-aminocoumarins derivatives against dopamine D3 receptors (D3R) of humans have been carried out to find out its therapeutic prospects for neuropsychiatric pharmacotherapy. Dopamine is a vital neurotransmitter in the human central nervous system that modulates cognitive and emotional functions through the activation of dopamine receptors, a class of the G protein-coupled receptor (GPCR) superfamily.²⁴ Blockage of dopamine D3 receptors (D3R) has been proved to be effective for potential pharmacotherapy for Schizophrenia, Parkinson's disease, enhancement of cognition and also in several neuropsychiatric disorders especially in drug addiction.²⁵

Taking advantage of the experimentally determined structure of human D3R (PDB Id: 3PBL),²⁶ the potentiality of our synthesized compounds as D3R inhibitors were studied through docking studies. Docking serves as a computational tool to understand the interactions between the protein and ligand.²⁷ Investigation on the structural details of the interactions between D3R and synthesized compounds corroborate with the importance of the inhibitors binding at the extracellular binding pocket of D3R.

Our synthesized compounds had better binding affinity than the co-crystallized known inhibitor, eticlopride (PDB Ligand ID: ETQ) (see Table SI2†). The compounds of series 5 showed better predicted inhibition efficacy as compared to the series of compounds 4. Surprisingly, compound 4f also showed comparable efficacy. This phenomenon may rise to the orientation of the tetrahydropyrido[2,3-c]coumarin ring in the vicinity of the extracellular binding pocket of D3R. Most of the 5 series compounds bound with the specific orientation at the proximity of highly conserved residues Asp110, Val111, Ser192, Phe345 and Tyr373 that bound tightly in the hydrophobic-cavity,²⁶ which reflects that these compounds may exhibit better inhibition. Pi interaction was observed with the conserved Phe345 with the individual aromatic ring of the synthesized compounds. The poor binding affinity of the compounds 5h, 5o and 5q which have a furfuryl ring instead of a benzene ring reflects the requirement of the orientation for the better binding. The best hit was found to be compound 5r which has the necessary above mentioned interactions (Fig. 4) and also has a hydrogen bond between the nitro group of the individual aromatic ring and the conserved Ser192 of D3R. To summarize our docking analysis, the results were comparable with the theoretical studies reported in literature²⁸ and also demonstrate the necessity of orientation and aromaticity of the potential inhibitors at the extracellular binding pocket of D3R (see Table SI2† in ESI).

Fig. 4 Interaction mode of the best hit 5r with dopamine D3 receptor. H-bond is depicted as green dots while pi interactions are depicted as ray lines.

Conclusion

In conclusion, we have demonstrated that hydrated ferric sulfate is an efficient catalyst for inducing Povarov reactions for the one-pot synthesis of furo- and tetrahydropyrido[2,3-c]coumarins derivatives from 3-aminocoumarins, aromatic aldehydes and cyclic ethers. In comparison to Yb(OTf)₃, hydrated ferric sulfate is cheaper and it provides improved yields. The present protocol is a more generalized one as it works with a wide variety of aromatic aldehydes and also gives good diastereoselectivities like other Lewis acid catalyzed Povarov reactions. Moreover, it was observed that the attack of the N-arylimine took place exclusively from the endo-face of the dienophiles, resulting in predominant formation of endo–exo adducts over endo–endo adducts, which was further confirmed through single XRD data and ¹H-NMR spectra. From the docking studies, it was found that some of the synthesized tetrahydropyrido[2,3-c]coumarin derivatives display inhibition activity against human dopamine D3 receptor, which might be the potential lead molecules for antipsychotic drugs, which is under investigation and the successful result will be disclosed later on.

Experimental section

Melting points were recorded on a melting point apparatus and are uncorrected. IR spectra were recorded on IR spectrophotometer. ¹H and ¹³C NMR spectra were recorded on NMR spectrometer by using TMS as internal reference; chemical shifts (δ scale) are reported in parts per million (ppm). Elemental analyses were carried out using CHNS/O analyzer. Column chromatographic separations were performed using silica gel (60–120 mesh). The X-ray crystal structures were determined with a XRD diffractometer.

Typical procedure for Povarov reaction

Into a 25 mL round bottom flask, a mixture of 3-aminocoumarin (0.161 g, 1 mmol) and benzaldehyde (0.106 g, 1 mmol) was taken in 3 mL of acetonitrile and the resulting solution stirred at rt for 10 min. Then, dihydropyran (100 μL, 1.1 mmol) and hydrated ferric sulfate (42 mg, 10 mol%) were added successively. Finally, the reaction mixture was refluxed on a pre-heated oil-bath and the progress of the reaction was monitored by TLC from time to time. After completion of the reaction, the solvent was removed and the residue was extracted with dichloromethane (2 × 10 mL). The organic extract was washed with water and dried over anhydrous Na₂SO₄. The solvent was removed in a rotatory evaporator and the crude product was purified through a silica gel column. The product was eluted using a mixture of hexane and ethyl acetate (98 : 02) as eluent. The less polar product 5a was eluted first and then product 4a was isolated. The overall yield was 81%.

Compound (4a). White solid (0.218 g, 65.7%). Mp. 243.6 °C; R_f (5% ethyl acetate/hexane) 0.21; anal. calcd for C₂₁H₁₉NO₃ (333.38): C, 75.66; H, 5.74; N, 4.20. Found C, 75.78; H, 5.83; N, 4.11. IR (KBr): 1629, 1707, 2841, 2924, 3407 cm⁻¹. ¹H NMR (400 MHz, CDCl₃): δ = 1.38–1.42 (m, 1H), 1.52–1.58 (m, 1H), 1.74 (tt, J = 4.4, 14.0 Hz, 1H), 1.90 (qt, J = 4.0, 12.8 Hz, 1H), 2.09–2.04 (m, 1H), 3.79 (td, J = 2.4, 11.2, Hz, 1H), 4.16 (dd, J = 4.0, 10.8 Hz, 1H), 4.67 (d, J = 2.8 Hz, 1H), 4.73 (d, J = 11.6 Hz, 1H), 5.10 (s, 1H), 7.20–7.28 (m, 3H), 7.33–7.42 (m, 5H), 7.53–7.56 (m, 1H) ppm. ¹³C NMR (400 MHz, CDCl₃): δ = 21.96, 23.48, 38.49, 54.44, 69.26, 69.98, 114.24, 116.54, 120.73, 121.80, 124.91, 126.06, 128.0 (2C), 128.57, 129.01 (2C), 130.26, 140.33, 148.26, 158.98 ppm. MS calcd for C₂₁H₁₉NO₃ [MH]⁺ 334.1365; found 334.1438.

Compound 5a. White solid (0.051 g, 15.3%). Mp. 188–189 °C; R_f (5% ethyl acetate/hexane) 0.27; anal. calcd for C₂₁H₁₉NO₃ (333.38): C, 75.66; H, 5.74; N, 4.20. Found C, 75.80; H, 5.84; N, 4.09. IR (KBr): 1613, 1718, 2841, 2949, 3422 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ = 1.39–1.73 (m, 4H), 2.24–2.34 (m, 1H), 3.17 (t, J = 11.2 Hz, 1H), 3.61 (d, J = 11.2 Hz, 1H), 4.69 (s, 1H), 5.05 (s, 1H), 5.50 (d, J = 5.6 Hz, 1H), 7.22–7.42 (m, 8H), 8.22 (d, J = 7.6 Hz, 1H) ppm. ¹³C NMR (400 MHz, CDCl₃): δ = 19.42, 24.57, 38.47, 59.18, 62.49, 72.12, 115.49, 116.47, 120.65, 124.71, 124.89, 126.49, 126.94 (2C), 128.04, 128.73 (2C), 131.26, 139.42, 148.23, 158.53 ppm.

Compound (4b). White solid (0.224 g, 64.7%). Mp. 204.4 °C; R_f (5% ethyl acetate/hexane) 0.21; anal. calcd for C₂₂H₂₁NO₃ (347.41): C, 76.06; H, 6.09; N, 4.03. Found C, 76.20; H, 6.14; N, 4.14. IR (KBr): 1626, 1712, 2851, 2934, 3402 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ = 1.39 (d, J = 13.2 Hz, 1H), 1.56 (d, J = 14.0 Hz, 1H), 1.68–1.78 (m, 1H) 1.82–1.94 (m, 1H), 2.00–2.06 (m, 1H), 2.37 (s, 3H), 3.78 (t, J = 11.2 Hz, 1H), 4.11–4.18 (m, 1H), 4.67 (s, 1H), 4.70 (d, J = 11.6 Hz, 1H), 5.07 (s, 1H), 7.17–7.31 (m, 7H), 7.54 (d, J = 7.2 Hz, 1H) ppm. ¹³C NMR (400 MHz, CDCl₃): δ = 21.34, 21.99, 23.55, 38.49, 54.17, 69.29, 70.08, 114.13, 116.57, 120.82, 121.80, 124.93, 126.02, 127.92 (2C), 129.70 (2C), 130.34, 137.30, 138.33, 148.29, 159.04 ppm. MS calcd for C₂₂H₂₁NO₃ [MH]⁺ 348.1521; found 348.1612.

Compound (5b). White solid (0.067 g, 19.3%). Mp. 173.6 °C; R_f (5% ethyl acetate/hexane) 0.29; anal. calcd for C₂₂H₂₁NO₃ (347.41): C, 76.06; H, 6.09; N, 4.03. Found C, 76.16; H, 6.11; N, 4.07. IR (KBr): 1613, 1717, 2851, 2923, 3427 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ = 1.42–1.68 (m, 4H), 2.22–2.30 (m, 1H), 2.37 (s, 3H), 3.17 (t, J = 11.2 Hz, 1H), 3.62 (dd, J = 3.6, 12.8 Hz, 1H), 4.66 (d, J = 1.6 Hz, 1H), 5.02 (s, 1H), 5.50 (d, J = 5.6 Hz, 1H), 7.18–7.34 (m, 7H), 8.22 (d, J = 7.6 Hz, 1H) ppm. ¹³C NMR (400 MHz, CDCl₃): δ = 19.46, 21.34, 24.68, 38.61, 59.03, 62.50, 72.21, 115.45, 116.52, 120.76, 124.77, 124.92, 126.48, 126.88 (2C), 129.43 (2C), 131.40, 136.39, 137.82, 148.27, 158.61 ppm.

Compound (4c). White solid (0.282 g, 73.1%). Mp. 226.4 °C; R_f (5% ethyl acetate/hexane) 0.21; anal. calcd for C₂₁H₁₈ClNO₃ (367.83): C, 68.57; H, 4.93; N, 3.81. Found C, 68.68; H, 4.86; N, 3.92. IR (KBr): 1628, 1716, 2851, 2934, 3399 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ = 1.40–1.46 (m, 1H), 1.50–1.55 (m, 1H), 1.71–1.93 (m, 2H), 2.00–2.08 (m, 1H), 3.80 (td, J = 11.6, 2.4 Hz, 1H), 4.12–4.18 (m, 1H), 4.68 (d, J = 2.8 Hz, 1H), 4.73 (d, J = 11.6 Hz, 1H), 5.06 (s, 1H), 7.24–7.29 (m, 3H), 7.32–7.40 (m, 4H), 7.52–7.57 (m, 1H) ppm. ¹³C NMR (400 MHz, CDCl₃): δ = 21.97, 23.50, 38.65, 53.95, 69.31, 69.92, 114.70, 116.65, 120.59, 121.88, 125.0, 126.35, 129.28 (2C), 129.38 (2C), 130.19, 134.37, 138.92, 148.39, 158.97 ppm.

Compound (5c). White solid (0.051 g, 13.9%). Mp. 163.2 °C; R_f (5% ethyl acetate/hexane) 0.29; anal. calcd for C₂₁H₁₈ClNO₃ (367.83): C, 68.57; H, 4.93; N, 3.81. Found C, 68.74; H, 4.86; N, 3.98. IR (KBr): 1615, 1713, 2852, 2925, 3387 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ = 1.28–1.61 (m, 3H); 2.16–2.22 (m, 1H), 3.11 (t, J = 10.8 Hz, 1H), 3.54 (d, J = 11.2 Hz, 1H), 4.28 (d, J = 5.6 Hz, 1H), 4.58 (d, J = 1.6 Hz, 1H), 4.91 (s, 1H), 5.39 (d, J = 5.2 Hz, 1H), 7.07–7.28 (m, 7H), 8.12 (d, J = 7.6 Hz, 1H) ppm. ¹³C NMR (400 MHz, CDCl₃): δ = 19.46, 24.43, 38.30, 58.64, 62.63, 71.96, 115.84, 116.52, 120.50, 124.96, 125.37, 126.24, 126.70, 128.35 (2C), 128.9 (2C), 129.2, 131.0, 138.1, 148.3, 158.5 ppm.

Compound (4d). White solid (0.284 g, 68.8%). Mp. 245.2 °C; R_f (5% ethyl acetate/hexane) 0.16; anal. calcd for C₂₁H₁₈BrNO₃ (412.28): C, 61.18; H, 4.40; N, 3.40. Found C, 61.34; H, 4.48; N, 3.52. IR (KBr): 1626, 1715, 2849, 2937, 3396 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ = 1.43–1.47 (m, 1H), 1.68–1.85 (m, 2H), 1.92–1.98 (m, 1H), 3.22 (q, J = 14.8, 7.6 Hz, 1H), 3.72 (td, J = 2.4, 11.2 Hz, 1H), 4.06–4.12 (m, 1H), 4.60 (d, J = 3.2 Hz, 1H), 4.63 (d, J = 11.6 Hz, 1H), 4.98 (s, 1H), 7.16–7.24 (m, 7H), 7.45 (d, J = 8.4 Hz, 1H) ppm. ¹³C NMR (400 MHz, CDCl₃): δ = 21.95, 23.48, 38.59, 53.99, 69.31, 69.88, 114.72, 116.64, 120.56, 121.87, 122.46, 125.01, 126.36, 129.72 (2C), 130.15, 132.22 (2C), 139.42, 148.36, 158.96 ppm. MS calcd for C₂₁H₁₈BrNO₃ [MH]⁺ 412.0470; found 412.0494.

Compound (5d). White solid (0.071 g, 17.2%). Mp. 184.4 °C; R_f (5% ethyl acetate/hexane) 0.24; anal. calcd for C₂₁H₁₈BrNO₃ (412.28): C, 61.18; H, 4.40; N, 3.40. Found C, 61.28; H, 4.46; N, 3.54. IR (KBr): 1614, 1707, 2853, 2923, 3383 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ = 1.32–1.39 (m, 2H); 1.42–1.58 (m, 2H), 2.13–2.22 (m, 1H), 3.12 (t, J = 11.2 Hz, 1H), 3.54–3.57 (m, 1H), 4.58 (s, 1H), 4.92 (s, 1H), 5.41 (d, J = 5.6 Hz, 1H), 7.16–7.26 (m, 5H), 7.44 (d, J = 8.4 Hz, 2H), 8.14 (d, J = 8.0 Hz, 1H), ¹³C NMR (400 MHz, CDCl₃): δ = 19.50, 24.48, 38.36, 58.77, 62.67, 72.01, 116.58, 120.53, 121.91, 124.75, 125.0, 126.76, 128.72 (2C), 131.07, 131.90 (2C), 138.60, 148.39, 158.54 ppm.

Compound (4e). White solid (0.256 g, 73.1%). Mp. 204 °C; R_f (5% ethyl acetate/hexane) 0.16; anal. calcd for C₂₁H₁₈FNO₃ (351.37): requires C, 71.78; H, 5.16; N, 3.99. Found C, 71.90; H, 5.22; N, 3.84. IR (KBr): 1634, 1714, 2830, 2935, 3421 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ = 1.39–1.42 (m, 1H); 1.50–1.54 (m, 1H), 1.71–1.93 (m, 2H), 2.00–2.04 (m, 1H), 3.79 (td, J = 2.0, 11.6 Hz, 1H), 4.13–4.17 (m, 1H), 4.67 (d, J = 3.2 Hz, 1H), 4.72 (d, J = 11.6 Hz, 1H), 5.05 (s, 1H), 7.08 (t, J = 8.8 Hz, 2H), 7.21–7.28 (m, 3H), 7.35–7.39 (m, 2H), 7.52–7.55 (m, 1H) ppm. ¹³C NMR (400 MHz, CDCl₃): δ = 21.97, 23.44, 38.63, 53.78, 69.27, 69.92, 114.58, 115.84, 116.05, 116.58, 120.61, 121.85, 124.96 (2C), 126.24 (2C), 129.85, 130.17, 136.12, 148.32, 158.96 ppm. MS calcd for C₂₁H₁₈FNO₃ [MH]⁺ 352.1271; found 352.1352.

Compound (5e). Semi solid (0.048 g, 13.9%). R_f (5% ethyl acetate/hexane) 0.20; anal. calcd for C₂₁H₁₈FNO₃ (351.37): requires C, 71.78; H, 5.16; N, 3.99. Found C, 71.94; H, 5.24; N, 3.82. IR (KBr): 1509, 1626, 1699, 2925, 3408 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ = 1.71–1.42 (m, 4H), 2.31–2.22 (m, 1H), 3.19 (t, J = 11.6 Hz, 1H), 3.64–3.61 (m, 1H), 4.68 (d, J = 2.0 Hz, 1H), 4.99 (s, N H, 1H), 5.48 (d, J = 5.2 Hz, 1H), 7.40–7.16 (m, 7H), 8.21 (d, J = 8.0 Hz, 1H) ppm. IR = 3408, 2925, 1699, 1626, 1509 cm⁻¹.

Compound (4f). White solid (0.316 g, 87%). Mp. 221.2 °C; R_f (5% ethyl acetate/hexane) 0.19; anal. calcd for C₂₂H₂₁NO₄ (363.41): C, 72.71; H, 5.82; N, 3.85. Found C, 72.82; H, 5.94; N, 3.94. IR (KBr): 1628, 1716, 2849, 2928, 3402 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ = 1.32 (d, J = 13.2 Hz, 1H); 1.49 (d, J = 13.6 Hz, 1H), 1.64–1.71 (m, 1H), 1.75–1.85 (m, 1H), 1.94–1.97 (m, 1H), 3.71 (t, J = 11.6 Hz, 1H), 3.75 (s, 3H), 4.08 (d, J = 11.2 Hz, 1H), 4.62–4.64 (m, 2H), 4.98 (s, 1H), 6.84 (d, J = 7.6 Hz, 2H), 7.16–7.19 (m, 3H), 7.24 (d, J = 7.6 Hz, 2H), 7.47 (d, J = 7.2 Hz, 1H), ¹³C NMR (400 MHz, CDCl₃): δ = 21.98, 23.54, 38.57, 53.83, 55.53, 69.34, 70.12, 114.19, 114.40 (2C), 116.59, 120.81, 121.79, 124.95, 126.06, 129.12 (2C), 130.36, 132.28, 148.28, 159.36, 159.81 ppm.

Compound (4g). White solid (0.350 g, 89%). Mp. 194.7 °C; R_f (5% ethyl acetate/hexane) 0.16; anal. calcd for C₂₃H₂₃NO₅ (393.43): C, 70.21; H, 5.89; N, 3.56. Found C, 70.38; H, 5.96; N, 3.67. IR (KBr): 1627, 1717, 2841, 2951, 3401 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ = 1.38 (d, J = 12.4 Hz, 1H), 1.52–1.58 (m, 1H), 1.74 (tt, J = 4.8, 13.2 Hz, 1H), 1.92–2.10 (m, 2H), 3.76 (td, J = 2.4, 11.6 Hz, 1H), 3.82 (s, 3H, OMe), 3.83 (s, 3H, OMe), 4.12 (d, J = 7.6 Hz, 1H), 4.68 (d, J = 2.8 Hz, 1H), 4.95 (s, 1H), 5.21 (bs, 1H), 6.49 (d, J = 2.4 Hz, 1H), 6.53 (dd, J = 2.0, 8.4 Hz, 1H), 7.20–7.28 (m, 3H), 7.32 (d, J = 8.4 Hz, 1H), 7.57 (d, J = 8 Hz, 1H) ppm. ¹³C NMR (400 MHz, CDCl₃): δ = 22.23, 23.87, 38.23, 55.54, 55.57, 69.08, 70.27, 98.52, 105.22, 113.65, 116.45, 121.08, 121.20, 121.80, 124.83, 125.71 (2C), 129.08, 130.68, 148.16, 158.98, 159.11, 160.68 ppm.

Compound (4h). White solid (0.278 g, 86%). Mp. 245.2 °C; R_f (5% ethyl acetate/hexane) 0.16; anal. calcd for C₁₉H₁₇NO₄ (323.34): C, 70.58; H, 5.30; N, 4.33. Found C, 70.73; H, 5.38; N, 4.22. IR (KBr): 1631, 1714, 2940, 3392 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ = 1.45 (d, J = 6.8 Hz, 1H), 1.62–1.68 (m, 1H), 1.80–1.96 (m, 2H), 2.27 (d, J = 11.6 Hz, 1H), 3.79 (t, J = 11.2 Hz, 1H), 4.14 (d, J = 11.2 Hz, 1H), 4.71 (d, J = 3.2 Hz, 1H), 4.90 (d, J = 11.6 Hz, 1H), 5.09 (s, 1H, N H), 6.41 (s, 2H), 7.18–7.29 (m, 3H), 7.44 (s, 1H), 7.46–7.60 (m, 1H) ppm. ¹³C NMR (400 MHz, CDCl₃): δ = 21.97, 23.84, 36.74, 48.26, 69.22, 69.84, 108.80, 110.57, 114.53, 116.65, 120.59, 121.85, 124.98, 126.32, 129.83, 142.88, 148.37, 153.07, 158.91 ppm. MS calcd for C₁₉H₁₇NO₄ [MH]⁺ 324.1158; found 324.1185.

Compound (4i). White solid (0.238 g, 62.2%). Mp. 198 °C (reported¹⁹ Mp. 240–241 °C); R_f (5% ethyl acetate/hexane) 0.20; anal. calcd for C₂₅H₂₁NO₃ (383.45): requires C, 78.30; H, 5.52; N, 3.65. Found C, 78.44; H, 5.60; N, 3.76. IR (KBr): 1506, 1628, 1704, 2840, 2938, 3362 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ = 1.42–1.38 (m, 1H); 1.53–1.56 (m, 1H), 1.71–1.78 (m, 1H), 1.94–1.99 (m, 1H), 2.17–2.20 (m, 1H), 3.81 (t, J = 11.2 Hz, 1H), 4.18–4.20 (m, 1H), 4.72 (s, 1H), 4.91 (d, J = 11.2 Hz, 1H), 5.19 (s, 1H), 7.26–7.28 (m, 3H), 7.56–7.58 (m, 4H), 7.85–7.90 (m, 4H) ppm. ¹³C NMR (400 MHz, CDCl₃): δ = 21.95, 23.47, 38.33, 54.54, 69.24, 69.91, 114.39, 116.51, 120.68, 121.82, 124.89, 125.12, 126.08, 126.37, 126.54, 127.43, 127.88, 127.98, 128.89, 130.23, 133.38, 133.47, 137.62, 148.25, 158.96 ppm. MS calcd for C₂₅H₂₁NO₃ [MH]⁺ 384.1521; found 384.1604.

Compound (5i)¹⁹. Semi solid (reported solid, Mp. 201–202 °C); (0.045 g, 11.8%). R_f (5% ethyl acetate/hexane) 0.26; anal. calcd for C₂₅H₂₁NO₃ (383.45): requires C, 78.30; H, 5.52; N, 3.65. Found C, 78.46; H, 5.58; N, 3.80. IR (KBr): 1088, 1261, 1613, 1710, 2923, 3413 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ = 1.71–1.41 (m, 4H); 2.42–2.39 (m, 1H), 3.20 (t, J = 11.2 Hz, 1H), 3.65–3.61 (m, 1H), 4.86 (s, 1H), 5.18 (s, N H, 1H), 5.57 (d, J = 5.6 Hz, 1H), 7.55–7.46 (m, 4H), 7.92–7.81 (m, 5H), 8.08 (s, 1H), 8.25 (d, J = 7.6 Hz, 1H) ppm.

Compound (4j). Yellow solid (0.195 g, 51.6%). Mp. 267 °C; R_f (5% ethyl acetate/hexane) 0.14; anal. calcd for C₂₁H₁₈N₂O₅ (378.38): C, 66.66; H, 4.79; N, 7.40. Found. C, 66.81; H, 4.86; N, 7.54. IR (KBr): 1343, 1513, 1634, 1713, 2845, 2945, 3393 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ = 1.46–1.49 (m, 2H), 1.78–1.93 (m, 2H), 2.07–2.12 (m, 1H), 3.82 (t, J = 11.2 Hz, 1H), 4.17–4.21 (m, 1H), 4.72 (d, J = 2.8 Hz, 1H), 4.85 (d, J = 11.2 Hz, 1H), 5.10 (s, 1H, N H), 7.26–7.30 (m, 3H), 7.56–7.57 (m, 1H), 7.62 (d, J = 8.4 Hz, 2H), 8.28 (d, J = 8.8 Hz, 2H) ppm. HRMS calcd for C₂₁H₁₈N₂O₅ [MH]⁺ 379.1216; found 379.1279.

Compound (5j). Semi solid (0.061 g, 16.4%). R_f (5% ethyl acetate/hexane) 0.20; anal. calcd for C₂₁H₁₈N₂O₅ (378.38): C, 66.66; H, 4.79; N, 7.40. Found. C, 66.84; H, 4.88; N, 7.52. IR (KBr): 1345, 1513, 1626, 1715, 2926, 3396 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ = 1.72–1.42 (m, 4H), 2.41–2.31 (m, 1H), 3.23 (t, J = 10.8 Hz, 1H), 3.65–3.63 (m, 1H), 4.80 (d, J = 2.4 Hz, 1H), 5.07 (s, NH, 1H), 5.48 (d, J = 5.2 Hz, 1H), 7.33–7.17 (m, 5H), 7.54 (d, J = 8.8 Hz, 1H), 7.62 (d, J = 8.4 Hz, 1H) ppm.

Compound (4k). White solid (0.190 g, 59.5%). Mp. 168.9 °C; R_f (5% ethyl acetate/hexane) 0.29; anal. calcd for C₂₀H₁₇NO₃ (319.3539): C, 75.22; H, 5.37; N, 4.39. Found C, 75.36; H, 5.44; N, 4.52. IR (KBr): 1708, 2873, 2923, 3405 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ = 1.76–1.83 (m, 1H); 2.06–2.16 (m, 1H), 2.46–2.53 (m, 1H), 3.79 (d, J = 11.2 Hz, 1H), 3.94 (q, J = 6.0 Hz, 1H), 4.08 (q, J = 8.0 Hz, 1H), 4.73 (d, J = 5.2 Hz, 1H), 5.26 (s, 1H), 7.25–7.29 (m, 3H), 7.36–7.46 (m, 5H), 7.72–7.78 (m, 1H) ppm. ¹³C NMR (400 MHz, CDCl₃): δ = 28.49, 42.88, 57.58, 65.68, 72.88, 115.82, 116.52, 121.28, 123.13, 125.08, 126.69, 128.43 (2C), 128.81, 129.08 (2C), 130.85, 140.0, 148.35, 158.89 ppm.

Compound (5k). White solid (0.081 g, 25.5%). Mp. 163.7 °C; R_f (5% ethyl acetate/hexane) 0.24; anal. calcd for C₂₀H₁₇NO₃ (319.35): C, 75.22; H, 5.37; N, 4.39. Found C, 75.39; H, 5.46; N, 4.48. IR (KBr): 1632, 1700, 2895, 2929, 3362 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ = 1.57–1.64 (m, 1H); 2.15–2.25 (m, 1H), 2.91–2.98 (m, 1H), 3.77 (q, J = 6.4, 14.8 Hz, 1H), 3.89 (td, J = 8.4, 2.8 Hz, 1H), 4.70 (d, J = 2.8 Hz, 1H), 4.97 (s, 1H), 5.48 (d, J = 8 Hz, 1H), 7.2–7.305 (m, 3H), 7.35 (d, J = 7.2 Hz, 1H), 7.40 (t, J = 7.2 Hz, 2H), 7.48 (d, J = 7.2 Hz, 2H), 7.79–7.82 (m, 1H) ppm. ¹³C NMR (400 MHz, CDCl₃): δ = 25.28, 46.32, 57.19, 67.69, 73.04, 116.54, 118.62, 120.40, 124.41, 124.82, 126.67, 126.94, 128.26, 128.44, 129.02 (2C), 129.92, 140.54, 148.79, 158.98 ppm.

Compound (4l). White solid (0.199 g, 56.1%). Mp. 226–227 °C; R_f (5% ethyl acetate/hexane) 0.21; anal. calcd for C₂₀H₁₆ClNO₃ (353.80): C, 67.90; H, 4.56; N, 3.96. Found C, 67.99; H, 4.64; N, 4.08. IR (KBr): 1627, 1716, 2921, 3383 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ = 1.70–1.76 (m, 1H); 2.05–2.15 (m, 1H), 2.40–2.46 (m, 1H), 3.76 (d, J = 7.2 Hz, 1H), 3.90–3.96 (m, 1H), 4.0–4.10 (m, 1H), 4.70 (d, J = 4.8 Hz, 1H), 5.22 (s, 1H), 7.26–7.28 (m, 3H), 7.32–7.42 (m, 4H), 7.72–7.75 (m, 1H) ppm. ¹³C NMR (400 MHz, CDCl₃): δ = 28.37, 42.93, 56.97, 65.63, 72.74, 116.14, 116.49, 121.06, 123.14, 125.08, 126.85, 129.23 (2C), 129.71 (2C), 130.65, 134.55, 138.52, 148.33, 158.76 ppm. HRMS calcd for C₂₀H₁₆ClNO₃ [MH]⁺ 354.0819; found 354.0808.

Compound (5l). White solid (0.081 g, 22.9%). Mp. 176–177 °C; R_f (5% ethyl acetate/hexane) 0.16; anal. calcd for C₂₀H₁₆ClNO₃ (353.80): C, 67.90; H, 4.56; N, 3.96. Found C, 68.08; H, 4.64; N, 4.09. IR (KBr): 1626, 1710, 2868, 2928, 3368 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ = 1.55–1.66 (m, 1H), 2.11–2.21 (m, 1H), 2.87–2.93 (m, 1H), 3.77 (q, J = 8.4 Hz, 1H), 3.89 (t, J = 8.4 Hz, 1H), 4.68 (s, 1H), 4.91 (s, 1H), 5.47 (d, J = 8.0 Hz, 1H), 7.25–7.32 (m, 3H), 7.38 (d, J = 8.4 Hz, 2H), 7.42 (d, J = 7.6 Hz, 2H), 7.80 (d, J = 8.4 Hz, 1H) ppm.

Compound (4m). White solid (0.219 g, 55.1%). Mp. 237–238 °C; R_f (5% ethyl acetate/hexane) 0.21; anal. calcd for C₂₀H₁₆BrNO₃ (398.25): C, 60.32; H, 4.05; N, 3.52. Found C, 60.48; H, 4.15; N, 3.68. IR (KBr): 1627, 1712, 2917, 3380 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ = 1.71–1.78 (m, 1H), 2.07–2.16 (m, 1H), 2.41–2.47 (m, 1H), 3.76 (d, J = 11.2 Hz, 1H), 3.94 (q, J = 9.2 Hz, 1H), 4.08 (q, J = 8.4 Hz, 1H), 4.71 (d, J = 5.2 Hz, 1H), 5.22 (s, 1H), 7.27–7.32 (m, 5H), 7.54 (d, J = 8.4 Hz, 2H), 7.73–7.75 (m, 1H) ppm. ¹³C NMR (400 MHz, CDCl₃): δ = 28.41, 42.96, 57.09, 65.68, 72.77, 116.20, 116.56, 121.07, 122.74, 123.17, 125.14, 126.92, 130.07, 130.68, 132.25 (2C), 139.07 (2C), 148.39, 158.81 ppm.

Compound (5m). White solid (0.103 g, 25.9%). Mp. 168–169 °C; R_f (5% ethyl acetate/hexane) 0.16; anal. calcd for C₂₀H₁₆BrNO₃ (398.25): C, 60.32; H, 4.05; N, 3.52. Found C, 60.42; H, 4.11; N, 3.67. IR (KBr): 1710, 2871, 2917, 3368 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ = 1.45–1.53 (m, 1H), 2.06 (q, J = 9.6 Hz, 1H), 2.77–2.84 (m, 1H), 3.68 (q, J = 8.8, 1 Hz, 1H), 3.79 (td, J = 2.4, 11.6 Hz, 1H), 4.57 (d, J = 2.4 Hz, 1H), 4.83 (s, 1H), 5.37 (d, J = 8 Hz, 1H), 7.17–7.23 (m, 3H), 7.27 (d, J = 8.4 Hz, 2H), 7.44 (d, J = 8.4 Hz, 2H), 7.71 (d, J = 9.2 Hz, 1H) ppm. ¹³C NMR (400 MHz, CDCl₃): δ = 25.13, 46.01, 56.60, 67.54, 72.84, 116.49, 118.86, 120.16, 121.97, 124.41, 124.81, 127.08, 128.31 (2C), 129.58, 132.09 (2C), 139.58, 148.74, 158.82 ppm.

Compound (4n). White solid (0.214 g, 61.6%). Mp. 186–187 °C; R_f (5% ethyl acetate/hexane) 0.21; anal. calcd for C₂₁H₁₉NO₄ (349.38): C, 72.19; H, 5.48; N, 4.01. Found C, 72.32; H, 5.55; N, 3.90. IR (KBr): 1627, 1712, 2917, 3380 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ = 1.73–1.80 (m, 1H), 2.04–2.15 (m, 1H), 2.42–2.49 (m, 1H), 3.74 (d, J = 11.2 Hz, 1H), 3.83 (s, 3H), 3.88–3.95 (m, 1H), 4.06 (q, J = 8.0 Hz, 1H), 4.72 (d, J = 5.2 Hz, 1H), 5.22 (bs, 1H, N H), 6.93 (d, J = 8.4 Hz, 2H), 7.25–7.29 (m, 3H), 7.34 (d, J = 8.4, 2H), 7.72–7.75 (m, 1H) ppm. ¹³C NMR (400 MHz, CDCl₃): δ = 28.41, 42.73, 55.39, 56.81, 65.49, 72.81, 114.27 (2C), 115.61, 116.30, 121.22, 123.01, 124.90, 126.45, 129.37 (2C), 130.73, 131.85, 148.15, 158.70, 159.81 ppm.

Compound (5n). Semi solid (0.092 g, 26.4%). R_f (5% ethyl acetate/hexane) 0.26; anal. calcd for C₂₁H₁₉NO₄ (349.38): C, 72.19; H, 5.48; N, 4.01. Found C, 72.36; H, 5.54; N, 3.92. IR (KBr): 1626, 1715, 2932, 3394 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ = 1.68–1.60 (m, 1H), 2.22–2.10 (m, 1H), 2.94–2.88 (m, 1H), 3.74 (s, OMe, 3H), 3.77–3.70 (m, 1H), 4.21–4.15 (m, 1H), 4.47 (d, J = 4.8 Hz, 1H), 5.30 (d, J = 8.0 Hz, 1H), 6.82 (d, J = 8.4 Hz, 1H), 7.17–7.08 (m, 4H), 7.25–7.18 (m, 2H), 7.65–7.62 (m, 1H) ppm.

Compound (4o). White solid (0.145 g, 46.8%). Mp. 153–154 °C; R_f (5% ethyl acetate/hexane) 0.21; anal. calcd for C₁₈H₁₅NO₄ (309.32): C, 69.89; H, 4.89; N, 4.53. Found C, 69.99; H, 4.98; N, 4.68. IR (KBr): 1634, 1711, 2864, 2966, 3400 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ = 1.85–1.93 (m, 1H), 2.21–2.30 (m, 1H), 2.65–2.72 (m, 1H), 3.90–4.07 (m, 3H), 4.75 (d, J = 5.6 Hz, 1H), 5.28 (s, 1H), 6.37–6.40 (m, 2H), 7.27–7.29 (m, 3H), 7.43 (d, J = 2.0 Hz, 1H), 7.71–7.74 (m, 1H), ppm; ¹³C NMR (400 MHz, CDCl₃): δ = 28.84, 40.15, 50.78, 65.77, 72.42, 108.45, 110.57, 116.0, 116.48, 121.01, 123.15, 125.03, 126.79, 129.96, 142.97, 148.34, 152.85, 158.68 ppm.

Compound (5o). White solid (0.96 g, 31.2%). Mp. 162–163 °C; R_f (5% ethyl acetate/hexane) 0.16; anal. calcd for C₁₈H₁₅NO₄ (309.32): C, 69.89; H, 4.89; N, 4.53. Found C, 69.98; H, 4.92; N, 4.65. IR (KBr): 1634, 1715, 2929, 3375 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ = 1.88–1.96 (m, 1H), 2.21 (q, J = 8.8 Hz, 1H), 3.08–3.15 (m, 1H), 3.82–3.87 (m, 2H), 4.74 (d, J = 2 Hz, 1H), 5.02 (s, 1H, N H), 5.42 (d, J = 7.6 Hz, 1H), 6.38 (d, J = 7.6 Hz, 2H), 7.26–7.31 (m, 3H), 7.41 (s, 1H), 7.80 (dd, J = 7.2, 1.6 Hz, 1H), ¹³C NMR (400 MHz, CDCl₃): δ = 25.74, 42.81, 51.17, 67.38, 72.52, 110.61, 106.68, 116.53, 118.63, 120.24, 124.35, 124.83, 127.04, 129.46, 142.34, 148.78, 153.23, 158.71 ppm.

Compound (4p). White solid (0.270 g, 60.7%). Mp. 219–220 °C; R_f (5% ethyl acetate/hexane) 0.31; anal. calcd for C₂₁H₁₇BrClNO₃ (446.72): C, 56.46; H, 3.84; N, 3.14. Found C, 56.59; H, 3.92; N, 3.28. IR (KBr): 1627, 1731, 2854, 2953, 3382 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ = 1.42–1.47 (m, 1H), 1.52–1.56 (m, 1H), 1.74–1.90 (m, 2H), 2.01–2.05 (m, 1H), 3.82 (td, J = 2.4, 11.6 Hz, 1H), 4.18 (d, J = 9.2 Hz, 1H), 4.63 (d, J = 2.8 Hz, 1H), 4.75 (d, J = 11.2 Hz, 1H), 5.16 (s, 1H, N H), 7.15 (d, J = 8.8 Hz, 1H), 7.32–7.36 (m, 3H), 7.39 (d, J = 8.4 Hz, 2H), 7.62 (d, J = 2.4 Hz, 1H) ppm. ¹³C NMR (400 MHz, CDCl₃): δ = 21.82, 23.35, 38.40, 53.79, 69.29, 69.60, 113.12, 118.01, 118.17, 122.47, 124.31, 128.83, 129.28 (2C), 130.65, 134.41, 138.55, 147.0, 158.25 ppm. MS calcd for C₂₁H₁₇BrClNO₃ [MH]⁺ 446.0080; found 446.0204.

Compound (5p). Semi solid (0.090 g, 20.3%); R_f (5% ethyl acetate/hexane) 0.36; anal. calcd for C₂₁H₁₇BrClNO₃ (446.72): C, 56.46; H, 3.84; N, 3.14. Found C, 56.62; H, 3.94, N; 3.26. IR (KBr): 1085, 1498, 1623, 1714, 2856, 3379 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ = 1.68–1.41 (m, 4H), 2.38–2.19 (m, 1H), 3.17 (t, J = 11.6 Hz, 1H), 3.68–3.65 (m, 1H), 4.68 (d, J = 2.4 Hz, 1H), 5.08 (s, NH, 1H), 5.42 (d, J = 5.6 Hz, 1H), 7.58–7.22 (m, 6H), 8.21 (s, 1H) ppm.

Compound (4q). White solid (0.241 g, 60.1%). Mp. 176 °C; R_f (5% ethyl acetate/hexane) 0.29; anal. calcd for C₁₉H₁₆BrNO₄ (402.24): C, 56.73; H, 4.01; N, 3.48. Found C, 56.88; H, 4.08; N, 3.38. IR (KBr): 1628, 1721, 2944, 3405 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ = 1.43–1.50 (m, 1H), 1.61–1.67 (m, 1H), 1.84–1.90 (m, 2H), 2.23 (d, J = 11.2 Hz, 1H), 3.78 (td, J = 2.0, 11.6 Hz, 1H), 4.11 (dd, J = 2.0, 11.2 Hz, 1H), 4.61 (d, J = 2.4 Hz, 1H), 4.87 (d, J = 11.6 Hz, 1H), 5.17 (s, 1H, N H), 6.39–6.42 (m, 2H), 7.11 (d, J = 8.4 Hz, 1H), 7.30 (dd, J = 2.0, 8.8 Hz, 1H), 7.43 (s, 1H), 7.60 (d, J = 2.0 Hz, 1H) ppm; ¹³C NMR (400 MHz, CDCl₃): δ = 21.83, 23.69, 36.44, 48.12, 69.20, 69.56, 108.94, 110.56, 112.92, 118.0, 118.18, 122.49, 124.29, 128.80, 130.31, 142.95, 146.99, 152.63, 158.21 ppm.

Compound (5q). White solid (0.68 g, 16.94%). Mp. 176–177 °C; R_f (5% ethyl acetate/hexane) 0.21; anal. calcd for C₁₉H₁₆BrNO₄ (402.24): C, 56.73; H, 4.01; N, 3.48. Found C, 56.89; H, 4.08, N 3.60. IR (KBr): 1628, 1721, 2862, 2925, 2944, 3405 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ = 1.57–1.75 (m, 3H) 2.42–2.47 (m, 1H), 3.24 (t, J = 10.4 Hz, 1H), 3.67 (d, J = 12.0 Hz, 1H), 4.37 (d, J = 5.6 Hz, 1H), 4.72 (s, 1H), 5.18 (s, 1H), 5.29 (d, J = 5.2 Hz, 1H), 6.33–6.34 (m, 1H), 6.38 (d, J = 2 Hz, 1H), 7.17 (d, J = 8.8 Hz, 1H), 7.37 (dd, J = 2.4, 8.6, Hz, 1H), 7.38–7.41 (m, 1H), 8.26 (s, 1H) ppm.

Compound (4r). White solid (0.238, 60.8%). Mp. 246–247 °C; R_f (5% ethyl acetate/hexane) 0.23; anal. calcd for C₂₂H₂₀N₂O₅ (392.41): C, 67.34; H, 5.14; N, 7.14. Found C, 67.48; H, 5.22; N, 7.10. IR (KBr): 1341, 1525, 1635, 1733, 2943, 3369 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ = 1.42–1.48 (m, 1H), 1.56–1.64 (m, 1H), 1.75–1.94 (m, 2H), 2.05–2.11 (m, 1H), 2.39 (s, 3H), 3.88 (t, J = 3.2 Hz, 1H), 4.18 (d, J = 9.2 Hz, 1H), 4.72 (d, J = 2.0 Hz, 1H), 4.75 (d, J = 12.4 Hz, 1H), 5.28 (s, 1H, N H), 7.23 (d, J = 7.2 Hz, 2H), 7.28 (d, J = 8 Hz, 2H), 7.36 (d, J = 8.8 Hz, 1H), 8.08 (d, J = 8.8 Hz, 1H), 8.39 (s, 1H) ppm. ¹³C NMR (400 MHz, CDCl₃): δ = 21.36, 21.84, 23.36, 38.23, 54.19, 69.44, 69.71, 112.43, 117.44, 117.73, 120.71, 121.75, 127.87, 129.89, 131.39, 136.60, 138.73, 145.04, 151.39, 157.76 ppm. MS calcd for C₂₂H₂₀N₂O₅ [MH]⁺ 393.1372; found 393.1477.

Compound (4s). White solid (0.257 g, 64.8%). Mp. 190 °C; R_f (5% ethyl acetate/hexane) 0.21; anal. calcd for C₂₂H₂₀ClNO₄ (397.85) C 66.42; H, 5.07; N, 3.52. Found C, 66.60; H, 5.12; N, 3.39. IR (KBr): 1510, 1634, 1716, 3405 cm⁻¹; ¹H NMR (400 MHz, CDCl3): δ = 1.40 (d, J = 12.4 Hz, 1H); 1.50 (d, J = 13.2 Hz, 1H), 1.74–1.85 (m, 2H), 1.97–2.0 (m, 1H), 3.74–3.79 (m, 1H), 3.83 (s, 3H), 4.12–4.15 (m, 1H), 4.59 (s, 1H), 4.66 (d, J = 11.2 Hz, 1H), 5.00 (s, 1H), 6.74–6.81 (m, 1H), 6.95–6.98 (m, 1H), 7.17 (dd, J = 1.6, 8.8 Hz, 1H), 7.32–7.37 (m, 4H) ppm. ¹³C NMR (400 MHz, CDCl₃): δ = 21.87, 23.37, 38.52, 53.80, 55.78, 69.17, 69.87, 105.87, 112.32, 114.24, 117.26, 121.28, 129.16, 129.30, 130.36, 134.22, 138.84, 142.77, 156.66, 158.87 ppm. MS calcd for C₂₂H₂₀ClNO₄ [MH]⁺ 398.1081; found 398.1156.

Compound (5s). Semi solid (0.068 g, 17.2%); R_f (5% ethyl acetate/hexane) 0.26; anal. calcd for C₂₂H₂₀ClNO₄ (397.85) C 66.42; H, 5.07; N, 3.52. Found C, 66.62; H, 5.16; N, 3.34. IR (KBr): 1085, 1505, 1617, 1709, 2936, 3390 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ = 1.63–1.41 (m, 4H), 2.24–2.21 (m, 1H), 3.21 (t, J = 10.8 Hz, 1H), 3.64 (dd, J = 2.0, 9.6 Hz, 1H), 3.83 (s, OMe, 3H), 4.67 (d, J = 2.4 Hz, 1H), 5.02 (s, N H, 1H), 5.46 (d, J = 5.6 Hz, 1H), 6.88 (dd, J = 2.8, 8.8 Hz, 1H), 7.22 (d, J = 9.2 Hz, 1H), 7.39–7.32 (m, 4H), 7.75 (d, J = 2.8 Hz, 1H) ppm.

Docking studies

The dopamine D3 receptors (D3R) of human bound with eticlopride [PDB Id: 1PBL] were used for the docking study. Experimentally determined structure of D3R was preprocessed by the removal of the co-crystallized ligands and water molecules. The synthesized compounds were constructed and energy minimized in Chemoffice using MM force field with 500 iterations with a threshold gradient of 0.001 kJ mol⁻¹. In AutoDock tools, hydrogen and Gasteiger–Marsili charges were added on D3R followed by merging of non-polar hydrogens. Ligands were also processed using AutoLigand utility with all potential torsions.²⁹ The synthesized molecules were docked at the extracellular binding pocket of the preprocessed D3R in AutoDock4.2 for 100 independent runs using lamarckian genetic algorithm to identify the bound conformations of synthesized compounds.^30,31 With grid spacing of 0.375 Å, grid maps were generated for all the atom types of D3R and the synthesized compounds along with electrostatic and desolvation maps. Docking calculations were carried out with an initial population size of 300, 25 000 000 evaluations, and 27 000 generations. The bound conformation of synthesized compounds was selected according to their lowest free energy of binding from the largest cluster based on their positional RMSD (2 Å). The docking results were analyzed for all possible interactions using ‘analyze’ utility in AutoDock tools.

Acknowledgements

DKD and SS are thankful to CSIR, New Delhi, India for their research fellowships. The authors are also grateful to the Director, IIT Guwahati for providing general facilities to carry out the research work. We are thankful to DST for providing XRD facility under the FIST programme. We are thankful to the referees' for their valuable comments and suggestions. We would like to express our sincere thanks to Prof. David W. Knight, School of Chemistry, Cardiff University, UK for his valuable suggestions during manuscript preparation.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: ¹H, ¹³C NMR Spectra and crystallographic data in CIF. CCDC 811857 and 838311. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c3ra45174g

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