Polystyrene-Supported p-Toluenesulfonic Acid: A New, Highly Efficient, and Recyclable Catalyst for the Synthesis of Hydropyridine Derivatives under Solvent-Free Conditions

Mudumala Veeranarayana Reddy; Yeon Tae Jeong

doi:10.1055/s-0032-1317670

Synlett, Table of Contents

Synlett 2012; 23(20): 2985-2991
DOI: 10.1055/s-0032-1317670

letter

Polystyrene-Supported p-Toluenesulfonic Acid: A New, Highly Efficient, and Recyclable Catalyst for the Synthesis of Hydropyridine Derivatives under Solvent-Free Conditions

Authors

Mudumala Veeranarayana Reddy

Department of Image Science and Engineering, Pukyong National University, Busan 608-737, Korea Fax: +82(51)6296408 Email: ytjeong@pknu.ac.kr
Yeon Tae Jeong*

Department of Image Science and Engineering, Pukyong National University, Busan 608-737, Korea Fax: +82(51)6296408 Email: ytjeong@pknu.ac.kr

Abstract

All articles of this category

Abstract

A new environmentally benign method for the preparation of hydropyridine derivatives has been developed by a simple one-pot condensation reaction of dimidine, active methylene compounds with aldehydes, and ammonium acetate in the presence of polystyrene-supported p-toluenesulfonic acid as a highly active and reusable heterogeneous acid catalyst under solvent-free conditions at 60 °C. This new protocol has the advantages of easy availability, stability, reusability, and eco-friendliness of the catalyst, high to excellent yields, simple and easy experimental workup procedure.

Key words

polystyrene-supported p-toluenesulfonic acid - hydropyridine derivatives - active methylene compounds - solvent-free conditions

Full Text

References

References and Notes
1 Eicher T, Hauptmann S. The Chemistry of Heterocycles . Wiley-VCH; Weinheim: 2003

2a Klusa V. Drugs Future 1995; 20: 135
2b Bretzel RG, Bollen CC, Maeser E, Federlin KF. Am. J. Kidney Dis. 1993; 21: 54
2c Boer R, Gekeler V. Drugs Future 1995; 20: 499

3 Davis HL, Davis TE. Cancer Treat Rep. 1979; 63: 809
4 Pastan I, Gottesman MM. N. Engl. J. Med. 1987; 316: 1388
5 Mithu S, Pal AK. Tetrahedron Lett. 2011; 52: 4872
6 Saikia L, Dutta D, Dutta DK. Catal. Commun. 2012; 19: 1
7 Hong M, Chun C, Wen-Bin Y. J. Fluorine Chem. 2010; 131: 111
8 James LD, Richard AG, Surya KD. J. Mol. Catal. A: Chem. 2006; 256: 309
9 Rajendra S, Dipak K, Dhanunjaya Rao AV, Kaviraj Y, Chandrasekhar KB. J. Fluorine Chem. 2012; 135: 91
10 Kumar A, Maurya RA. Synlett 2008; 883
11 Ko S, Sastry MN. V, Lin C, Yao CF. Tetrahedron Lett. 2005; 46: 5771
12 Sabitha G, Reddy GS. K. K, Reddy CS, Yadav JS. Tetrahedron Lett. 2003; 44: 4129
13 Evans CG, Gestwicki JE. Org. Lett. 2009; 11: 2957
14 Pasunooti KK, Jensen CN, Chai H, Leow ML, Zhang DW, Liu XW. J. Comb. Chem. 2010; 12: 577
15 Debache A, Ghalem W, Boulcina R, Belfaitah A, Rhouati S, Carboni B. Tetrahedron Lett. 2009; 50: 5248
16 Siddaiah V, Basha GM, Rao GP, Prasad UV, Rao RS. Synth. Commun. 2012; 42: 627
17 Khabazzadeh H, Kermani ET, Afzali D, Amiri A, Jalaladini A. Arabian J. Chem. 2012; 5: 167
18 Farahnaz BK, Maryam H. Synth. React. Inorg., Met.-Org., Nano-Met. Chem. 2012; 42: 291
19 Montes-Avila J, Delgado-Vargas F, Díaz-Camacho SP, Rivero IA. RSC Advances 2012; 2: 1827
20 Ji SJ, Jiang ZQ, Lu J, Loh TP. Synlett 2004; 831
21 Martins MA. P, Frizzo CP, Moreira DN. Buriol L, Machado P. Chem. Rev. 2009; 109
22 Reddy MV, Lim KT, Kim JT, Jeong YT. J. Chem. Res. 2012; 36: 398
23 Reddy MV, Jeong YT. J. Fluorine Chem. 2012; 142: 45
24 Ley SV, Baxendale IR, Bream RN, Jackson PS, Leach AG, Longbottom DA, Nesi M, Scott JS, Storer RI, Taylor SJ. J. Chem. Soc., Perkin Trans. 1 2000; 3815
25 Shuttleworth SJ, Allin SM, Sharma PK. Synthesis 1997; 1217
26 Frechet JM. J, Darling P, Farrall MJ. J. Org. Chem. 1981; 46: 1728
27 Tamami B, Parvanak Borujeni K. Iran. Polym. J. 2009; 18: 191
28 Akela A, Moet A. Functionalized Polymers and Their Applications . Wiley; New York: 1990: 11
29 Roberto S, Alberto M, Delia M, Julia MA. G, Felix R. Adv. Synth. Catal. 2006; 348: 1841
30 Shinya I, Kei M, Shu K. Org. Biomol. Chem. 2003; 1: 2416
31 Reddy MV, Reddy GC. S, Jeong YT. Tetrahedron 2012; 68: 6820
32 Reddy MV, Dindulkar SD, Jeong YT. Tetrahedron Lett. 2011; 52: 4764
33 Synthesis of Ethyl-4-(2-fluoro-4-methoxyphenyl)-1,4,5,6,7,8-hexahydro-2,7,7-trimethyl-5-oxoquinoline-3-carboxylate (5a) A mixture of dimedone (1, 1 mmol), 2-fluoro-4-methoxybenzaldehyde (2a, 1 mmol), NH₄OAc (3, 1.5 mmol), ethyl acetoacetate (4, 1 mmol), and PS/PTSA (30 mg) was stirred at 60 °C under solvent-free conditions for 15 min (Table 3, entry 1). The progress of the reaction was monitored by TLC. After completion of the reaction, the mixture was washed with EtOAc and filtered to recover the catalyst. The filtrate was evaporated, and the crude product was recrystallized from EtOH to afford pure 5a in excellent yield (92%). The spent polymeric catalyst from different experiments was combined, washed with Et₂O, and dried overnight in a vacuum oven and reused. Yield 92%; white solid; mp 277–279 °C. ¹H NMR (400 MHz, CDCl₃): δ = 7.27–7.20 (q, 1 H), 6.62 (s, 1 H), 6.55 (dd, J = 2.5, 11.0 Hz, 1 H), 6.46 (dd, J = 2.2, 14.2 Hz, 1 H), 5.14 (s, 1 H), 4.06–4.01 (q, 2 H), 3.71 (s, 3 H), 2.29 (s, 3 H), 2.28 (d, J = 16.4 Hz, 2 H), 2.20 (d, J = 16.4 Hz, 2 H), 1.20 (t, J = 9.0 Hz, 3 H), 1.03 (s, 3 H), 0.93 (s, 3 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 195.5, 167.5, 159.1, 158.9, 148.8, 143.8, 131.6, 126.0, 125.9, 110.5, 109.2, 104.6, 101.2, 59.7, 55.3, 50.6, 40.8, 32.5, 31.7, 29.4, 26.8, 19.1, 14.0 ppm. ESI-HRMS: m/z calcd for C₂₂H₂₆FNO₄ [M + H⁺]: 387.1846; found: 387.1844. Ethyl-4-(3-fluoro-4-methylphenyl)-1,4,5,6,7,8-hexahydro-2,7,7-trimethyl-5-oxoquinoline-3-carboxylate (5b) Yield 90%; white solid; mp 251–253 °C. ¹H NMR (400 MHz, CDCl₃): δ = 7.13 (s, 1 H), 6.98 (d, J = 5.1 Hz, 2 H), 6.92 (d, J = 11.3 Hz, 1 H), 5.01 (s, 1 H), 4.08–4.05 (q, 2 H), 2.30 (s, 3 H), 2.28 (s, 3 H), 2.21 (d, J = 16.1 Hz, 2 H), 2.17 (d, J = 16.1 Hz, 2 H), 1.21 (t, J = 6.9 Hz, 3 H), 1.05 (s, 3 H), 0.93 (s, 3 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 195.8, 167.3, 162.3, 159.8, 149.3, 146.9, 143.6, 130.6, 123.3, 122.1, 114.4, 111.4, 105.5, 59.8, 50.7, 40.7, 36.1, 32.5, 29.3, 27.0, 19.1, 14.5, 14.1 ppm. ESI-HRMS: m/z calcd for C₂₂H₂₆FNO₃ [M + H⁺]: 371.1897; found: 371.1897. Ethyl-4-(4-fluoro-3-nitrophenyl)-1,4,5,6,7,8-hexahydro-2,7,7-trimethyl-5-oxoquinoline-3-carboxylate (5c) Yield 88%; yellow solid; mp 178–180 °C. ¹H NMR (400 MHz, CDCl₃): δ = 7.95 (dd, J = 2.2, 9.5 Hz, 1 H), 7.66–7.64 (m, 1 H), 7.15–7.10 (q, 1 H), 6.73 (s, 1 H), 5.10 (s, 1 H), 4.10–4.05 (q, 2 H), 2.39 (d, J = 16.2 Hz, 1 H), 2.38 (s, 3 H), 2.25 (d, J = 16.2 Hz, 2 H), 2.18 (d, J = 16.1 Hz, 1 H), 1.21 (t, J = 6.9 Hz, 3 H), 1.09 (s, 3 H), 0.94 (s, 3 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 195.5, 166.7, 155.2, 152.6, 149.1, 144.6, 144.4, 135.5, 125.1, 117.4, 110.9, 104.7, 104.7, 60.0, 50.5, 40.7, 36.4, 32.7, 29.2, 27.0, 19.3, 14.1 ppm. ESI-HRMS: m/z calcd for C₂₁H₂₃FN₂O₅ [M + H⁺]: 402.1591; found: 402.1590. Ethyl-4-(2,3-difluorophenyl)-1,4,5,6,7,8-hexahydro-2,7,7-trimethyl-5-oxoquinoline-3-carboxylate (5d) Yield 90%; white solid; mp 240–242 °C. ¹H NMR (400 MHz, CDCl₃): δ = 8.33 (s, 1 H), 7.01–6.98 (m, 1 H), 6.84–6.79 (m, 2 H), 5.15 (s, 1 H), 3.97–3.91 (q, 2 H), 2.29 (s, 3 H), 2.11 (d, J = 16.4 Hz, 2 H), 1.99 (d, J = 16.4 Hz, 2 H), 1.10 (t, J = 7.3 Hz, 3 H), 0.99 (s, 3 H), 0.85 (s, 3 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 194.5, 166.7, 149.4, 145.0, 136.5, 136.4, 125.1, 122.4, 113.8, 113.6, 109.1, 102.7, 58.9, 50.1, 39.5, 33.2, 31.2, 28.8, 26.3, 18.1, 13.4 ppm. Ethyl-4-(3,5-difluorophenyl)-1,4,5,6,7,8-hexahydro-2,7,7-trimethyl-5-oxoquinoline-3-carboxylate (5e) Yield 90%; white solid; mp 208–210 °C. ¹H NMR (400 MHz, CDCl₃): δ = 7.20 (s, 1 H), 6.86–6.81 (m, 2 H), 6.58–6.52 (m, 1 H), 5.06 (s, 1 H), 4.10–4.06 (q, 2 H), 2.30 (s, 3 H), 2.27 (d, J = 16.1 Hz, 2 H), 2.19 (d, J = 16.4 Hz, 2 H), 1.21 (t, J = 6.9 Hz, 3 H), 1.07 (s, 3 H), 0.94 (s, 3 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 195.8, 167.0, 163.9, 161.4, 150.9, 149.6, 144.6, 110.8, 104.8, 101.3, 59.9, 50.6, 40.6, 36.6, 32.5, 29.2, 27.0, 19.0, 14.1 ppm. ESI-HRMS: m/z calcd for C₂₁H₂₃F₂NO₃ [M + H⁺]: 375.1646; found: 375.1643. Ethyl-4-(4-chlorophenyl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate (5f) Yield 96%; white solid; mp 245–247 °C (244–246 °C).^{7 1}H NMR (400 MHz, CDCl₃): δ = 7.23 (dd, J = 2.2, 12.0 Hz, 2 H), 7.15 (dd, J = 2.2, 10.2 Hz, 2 H), 6.91 (s, 1 H), 5.02 (s, 1 H), 4.07–4.03 (q, 2 H), 2.34 (s, 3 H), 2.23 (d, J = 16.2 Hz, 2 H), 2.17 (d, J = 16.2 Hz, 2 H), 1.20 (t, J = 6.9 Hz, 3 H), 1.05 (s, 3 H), 0.91 (s, 3 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 194.56, 167.2, 144.9, 143.5, 131.7, 129.3, 127.9, 116.9, 108.8, 105.4, 53.7, 50.6, 41.0, 37.0, 32.5, 29.5, 27.6, 19.1, 14.5 ppm. Ethyl-4-(4-nitrophenyl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate (5g) Yield 94%; white solid; mp 242–244 °C (240–242 °C).^{19 1}H NMR (400 MHz, CDCl₃): δ = 8.08 (d, J = 8.0 Hz, 2 H), 7.50 (d, J = 8.2 Hz, 2 H), 6.91 (s, 1 H), 5.16 (s, 1 H), 4.08–4.05 (q, 2 H), 2.38 (s, 3 H), 2.25 (d, J = 17.2 Hz, 2 H), 2.14 (d, J = 16.2 Hz, 2 H), 1.19 (t, J = 6.2 Hz, 3 H), 1.07 (s, 3 H), 0.90 (s, 3 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 195.0, 164.9, 153.3, 149.0, 145.2, 143.0, 128.8, 123.2, 115.9, 106.8, 60.1, 50.5, 40.9, 37.2, 32.6, 29.4, 27.4, 19.4, 14.1 ppm. Ethyl-2,7,7-trimethyl-5-oxo-4-propyl-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate (5h) Yield 86%; white solid; mp 147–149 °C (148–150 °C).^{7 1}H NMR (400 MHz, CDCl₃): δ = 6.34 (s, 1 H), 4.22–4.11 (m, 2 H), 4.02 (t, J = 5.5 Hz, 1 H), 2.36 (d, J = 17.2 Hz, 2 H), 2.30 (s, 3 H), 2.23 (d, J = 17.2 Hz, 2 H), 1.40–1.32 (m, 2 H), 1.28 (t, J = 6.9 Hz, 3 H), 1.23–1.18 (m, 2 H), 1.09 (s, 6 H), 0.82 (t, J = 6.9 Hz, 3 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 194.5, 166.4, 149.4, 145.2, 115.8, 108.1, 58.1, 40.6, 38.6, 36.6, 34.4, 32.5, 29.2, 27.0, 20.3, 19.0, 14.5, 14.1 ppm. Ethyl-4-ethyl-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate (5i) Yield 88%; white solid; mp 144–146 °C (144–146 °C).^{7 1}H NMR (400 MHz, CDCl₃): δ = 6.44 (s, 1 H), 4.22–4.10 (m, 2 H), 4.01 (t, J = 5.2 Hz, 1 H), 2.35 (d, J = 16.2 Hz, 2 H), 2.31 (s, 3 H), 2.23 (d, J = 16.2 Hz, 2 H), 1.48–1.33 (m, 2 H), 1.27 (t, J = 7.2 Hz, 3 H), 1.09 (s, 6 H), 0.74 (t, J = 7.6 Hz, 3 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 195.5, 168.6, 148.4, 146.2, 114.8, 105.1, 58.0, 39.6, 36.7, 35.6, 30.5, 29.2, 27.4, 22.3, 19.0, 14.5, 10.3 ppm. Ethyl-2,7,7-trimethyl-5-oxo-4-(thiophen-2-yl)-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate (5j) Yield 88%; white solid; mp 239–241 °C (241–242 °C).^{8 1}H NMR (400 MHz, CDCl₃): δ = 8.76 (s, 1 H), 7.00–6.98 (m, 1 H), 6.80–6.75 (m, 2 H), 5.30 (s, 1 H), 4.12–4.10 (q, 2 H), 2.37 (d, J = 16.2 Hz, 2 H), 2.33 (s, 3 H), 2.23 and 2.15 (AB system, J = 19.2 Hz, 2 H), 1.25 (t, J = 6.9 Hz, 3 H), 1.08 (s, 3 H), 1.01 (s, 3 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 198.1, 167.4, 150.5, 147.9, 143.8, 125.2, 121.7, 118.2, 111.8, 105.5, 60.4, 50.6, 38.7, 31.3, 30.5, 28.5, 27.5, 19.5, 14.2 ppm. Methyl-4-(2-fluoro-4-methoxyphenyl)-1,4,5,6,7,8-hexahydro-2,7,7-trimethyl-5-oxoquinoline-3-carboxylate (5k) Yield 91%; white solid; mp 261–263 °C. ¹H NMR (400 MHz, CDCl₃): δ = 8.54 (s, 1 H), 7.16 (t, J = 8.4 Hz, 1 H), 6.53 (dd, J = 2.5, 10.9 Hz, 1 H), 6.43 (dd, J = 2.2, 14.2 Hz, 1 H), 5.07 (s, 1 H), 3.71 (s, 3 H), 3.56 (s, 3 H), 2.35 (d, J = 16.8 Hz, 2 H), 2.29 (s, 3 H), 2.03 (d, J = 16.2 Hz, 2 H), 1.06 (s, 3 H), 0.92 (s, 3 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 194.0, 167.1, 157.8, 148.8, 144.2, 130.5, 126.0, 109.1, 108.5, 102.7, 100.1, 99.9, 54.4, 49.9, 49.7, 38.2, 31.5, 30.2, 28.7, 26.0, 17.8 ppm. Methyl-4-(3-fluoro-4-methylphenyl)-1,4,5,6,7,8-hexahydro-2,7,7-trimethyl-5-oxoquinoline-3-carboxylate (5l) Yield 89%; white solid; mp 252–254 °C. ¹H NMR (400 MHz, CDCl₃): δ = 8.43 (s, 1 H), 7.00–6.94 (q, 2 H), 6.89 (d, J = 11.3 Hz, 1 H), 5.10 (s, 1 H), 3.63 (s, 3 H), 2.37–2.30 (m, 5 H), 2.23–2.10 (m, 5 H), 1.06 (s, 3 H), 0.92 (s, 3 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 194.5, 167.1, 161.3, 158.9, 148.8, 146.6, 144.5, 129.8, 122.3, 120.9, 113.4, 110.1, 50.2, 49.5, 39.5, 35.0, 31.6, 28.6, 26.2, 18.0, 13.3 ppm. ESI-HRMS: m/z calcd for C₂₁H₂₄FNO₃ [M + H⁺]: 357.1740; found: 357.1745. Methyl-4-(4-fluoro-3-nitrophenyl)-1,4,5,6,7,8-hexahydro-2,7,7-trimethyl-5-oxoquinoline-3-carboxylate (5m) Yield 85%; yellow solid; mp 192–194 °C. ¹H NMR (400 MHz, CDCl₃): δ = 7.92 (dd, J = 2.2, 9.1 Hz 1 H), 7.67–7.64 (m, 1 H), 7.15–7.10 (q, 1 H), 6.68 (s, 1 H), 5.11 (s, 1 H), 3.66 (s, 3 H), 2.35 (s, 3 H), 2.25 (d, J = 16.8 Hz, 2 H), 2.11 (d, J = 16.2 Hz, 2 H), 1.09 (s, 3 H), 0.94 (s, 3 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 195.5, 167.2, 155.2, 153.2, 149.0, 144.8, 135.5, 124.9, 117.6, 110.9, 104.5, 51.1, 50.5, 40.8, 36.2, 32.7, 29.2, 27.0, 19.4 ppm. Methyl-4-(2,3-difluorophenyl)-1,4,5,6,7,8-hexahydro-2,7,7-trimethyl-5-oxoquinoline-3-carboxylate (5n) Yield 89%; white solid; mp 255–257 °C. ¹H NMR (400 MHz, CDCl₃): δ = 8.69 (s, 1 H), 7.06–703 (q, 1 H), 6.92–6.88 (m, 2 H), 5.19 (s, 1 H), 3.56 (s, 3 H), 2.37 (d, J = 17.2 Hz, 2 H), 2.31 (s, 3 H), 2.17 (d, J = 16.1 Hz, 2 H), 1.06 (s, 3 H), 0.91 (s, 3 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 193.9, 166.7, 149.2, 136.2, 124.7, 123.3, 113.5, 113.3, 108.7, 102.1, 50.2, 49.8, 38.7, 31.5, 30.7, 28.6, 26.0, 17.8 ppm. ESI-HRMS: m/z calcd for C₂₀H₂₁F₂NO₃ [M + H⁺]: 361.1489; found: 361.1488. Methyl-4-(3,5-difluorophenyl)-1,4,5,6,7,8-hexahydro-2,7,7-trimethyl-5-oxoquinoline-3-carboxylate (5o) Yield 92%; white solid; mp 261–263 °C. ¹H NMR (400 MHz, CDCl₃): δ = 8.54 (s, 1 H), 6.82–6.79 (m, 2 H), 6.54–6.52 (m, 1 H), 5.02 (s, 1 H), 3.61 (s, 3 H), 2.37 (s, 3 H), 2.33 (d, J = 16.1 Hz, 2 H), 2.19 (d, J = 16.3 Hz, 2 H), 1.07 (s, 3 H), 0.92 (s, 3 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 194.6, 167.0, 163.8, 161.0, 151.2, 149.3, 145.4, 109.9, 102.8, 100.4, 50.2, 49.1, 39.6, 35.7, 31.8, 28.8, 26.6, 18.2 ppm. Dimethyl-4-(3-fluoro-4-methylphenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate (6a) Yield 93%; white solid; mp 159–161 °C. ¹H NMR (400 MHz, CDCl₃): δ = 7.00 (t, J = 8.0 Hz, 1 H), 6.94 (dd, J = 1.8, 9.5 Hz, 1 H), 6.88 (dd, J = 1.4, 12.8 Hz, 1 H), 5.90 (s, 1 H), 4.96 (s, 1 H), 3.65 (s, 6 H), 2.31 (s, 6 H), 2.18 (s, 3 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 167.9, 159.9, 147.2, 144.4, 130.8, 122.8, 114.0, 113.8, 103.4, 51.0, 38.7, 19.4, 14.1 ppm. ESI-HRMS: m/z calcd for C₁₈H₂₀FNO₄ [M + H⁺]: 333.1376; found: 331.1378. Dimethyl-4-(2-fluoro-4-methoxyphenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate (6b) Yield 89%; yellow solid; mp 170–172 °C. ¹H NMR (400 MHz, CDCl₃): δ = 7.16 (t, J = 8.8 Hz, 1 H), 6.56 (dd, J = 2.5, 11.0 Hz, 1 H), 6.48 (dd, J = 2.5, 14.6 Hz, 1 H), 5.67 (s, 1 H), 5.14 (s, 1 H), 3.74 (s, 3 H), 3.61 (s, 6 H), 2.31 (s, 6 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 168.0, 144.0, 131.5, 127.1, 109.9, 103.3, 101.4, 57.4, 50.9, 35.3, 19.4 ppm. ESI-HRMS: m/z calcd for C₁₈H₂₀FNO₅ [M + H⁺]: 349.1326; found: 349.1325. Dimethyl-4-(2-bromo-4-fluorophenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate (6c) Yield 90%; yellow solid; mp 154–156 °C. ¹H NMR (400 MHz, CDCl₃): δ = 7.18–7.09 (m, 3 H), 5.70 (s, 1 H), 5.18 (s, 1 H), 3.61 (s, 6 H), 2.31 (s, 6 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 167.6, 144.5, 132.3, 127.3, 119.1, 118.8, 102.3, 50.9, 34.3, 19.4. ppm. ESI-HRMS: m/z calcd for C₁₇H₁₇BrFNO₄ [M + H⁺]: 397.0325; found: 397.0328. Dimethyl-4-(2,3-difluorophenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate (6d) Yield 90%; yellow solid; mp 150–152 °C. ¹H NMR (400 MHz, CDCl₃): δ = 7.24–7.20 (m, 1 H), 6.75–6.63 (m, 2 H), 5.69 (s, 1 H), 5.18 (s, 1 H), 3.61 (s, 6 H), 2.31 (s, 6 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 167.7, 149.2, 144.4, 141.2, 123.4, 116.4, 103.4, 51.0, 38.8, 19.5 ppm. Dimethyl-4-(2,4-difluorophenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate (6e) Yield 91%; yellow solid; mp 160–162 °C. ¹H NMR (400 MHz, CDCl₃): δ = 8.92 (s, 1 H), 7.23–7.17 (1, 3 H), 7.02–6.91 (m, 2 H), 5.07 (s, 1 H), 3.49 (s, 6 H), 2.23 (s, 6 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 167.8, 163.2, 144.5, 131.5, 123.2, 110.9, 110.7, 102.5, 50.9, 34.0, 19.4 ppm. ESI-HRMS: m/z calcd for C₁₇H₁₇F₂NO₄ [M + H⁺]: 337.1126; found: 337.1124. Dimethyl-4-(3,4-difluorophenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate (6f) Yield 90%; yellow solid; mp 165–167 °C. ¹H NMR (400 MHz, CDCl₃): δ = 7.02–6.96 (m, 3 H), 5.74 (s, 1 H), 4.97 (s, 1 H), 3.65 (s, 6 H), 2.32 (s, 6 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 167.7, 148.2, 144.4, 140.2, 123.4, 116.5, 116.3, 103.4, 51.0, 38.8, 19.5 ppm. Diethyl-4-(4-fluoro-3-nitrophenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate (6g) Yield 90%; yellow solid; mp 133–135 °C. ¹H NMR (400 MHz, CDCl₃): δ = 7.94 (dd, J = 2.2, 9.1 Hz, 1 H), 7.58–7.56 (m, 1 H), 7.14–7.10 (m, 1 H), 5.99 (s, 1 H), 5.04 (s, 1 H), 4.14–4.08 (q, 4 H), 2.35 (s, 6 H), 1.23 (t, J = 6.9 Hz, 6 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 166.9, 155.3, 152.7, 145.0, 144.8, 135.3, 125.3, 117.4, 103.1, 60.0, 39.3, 19.5, 14.2 ppm. ESI-HRMS: m/z calcd for C₁₉H₂₁FN₂O₆ [M + H⁺]: 392.1384; found: 392.1382. Diethyl-4-(3-fluoro-4-methylphenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate (6h) Yield 93%; white solid; mp 113–115 °C. ¹H NMR (400 MHz, CDCl₃): δ = 6.99–6.89 (m, 3 H), 5.86 (s, 1 H), 4.96 (s, 1 H), 4.13–4.08 (q, 4 H), 2.31 (s, 6 H), 2.18 (s, 3 H), 1.23 (t, J = 7.3 Hz, 6 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 167.5, 147.5, 130.6, 123.1, 122.2, 114.3, 103.7, 59.7, 39.1, 19.4, 14.2, 14.1 ppm. ESI-HRMS: m/z calcd for C₂₀H₂₄FNO₄ [M + H⁺]: 361.1689; found: 361.1689. Diethyl-4-(3,4-difluorophenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate (6i) Yield 90%; white solid; mp 140–142 °C. ¹H NMR (400 MHz, CDCl₃): δ = 7.12–7.08 (m, 2 H), 6.92 (d, J = 7.3 Hz 1 H), 5.89 (s, 1 H), 5.02 (s, 1 H), 4.10–4.06 (q, 4 H), 2.30 (s, 6 H), 1.22 (t, J = 6.9 Hz, 6 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 166.7, 149.2, 144.2, 122.4, 116.9, 115.2, 102.9, 59.2, 39.8, 19.2, 142.2 ppm. 9-(2-Fluoro-4-methoxyphenyl)-3,4,6,7-tetrahydro-3,3,6,6-tetramethylacridine-1,8-(2H,5H,9H,10H)-dione (7a) Yield 95%; yellow solid; mp 240–242 °C. ¹H NMR (400 MHz, CDCl₃): δ = 9.32 (s, 1 H), 7.07 (t, J = 8.4 Hz, 2 H), 6.74 (d, J = 7.6 Hz, 1 H), 4.87 (s, 1 H), 3.67 (s, 3 H), 2.39 and 2.27 (AB system, J = 17.2 Hz, 4 H), 2.20 (d, J = 16.2 Hz, 2 H), 2.04 (d, J = 17.2 Hz, 2 H), 1.02 (s, 6 H), 0.90 (s, 6 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 194.1, 160.2, 154.9, 149.3, 131.8, 129.4, 118.2, 111.8, 110.5, 55.2, 50.2, 41.8, 32.0, 29.1, 28.0, 26.1 ppm. ESI-HRMS: m/z calcd for C₂₄H₂₈FNO₃ [M + H⁺]: 397.2053; found: 397.2053. 9-(4-Fluoro-3-nitrophenyl)-3,4,6,7-tetrahydro-3,3,6,6-tetramethylacridine-1,8-(2H,5H,9H,10H)-dione (7b) Yield 90%; yellow solid; mp 293–295 °C. ¹H NMR (400 MHz, CDCl₃): δ = 9.48 (s, 1 H), 7.82 (dd, J = 2.2, 9.5 Hz, 1 H), 7.60–7.57 (m, 1 H), 7.44–7.39 (m, 1 H), 4.88 (s, 1 H), 2.47 and 2.37 (AB system, J = 17.2 Hz, 4 H), 2.19 (d, J = 16.2 Hz, 2 H), 2.01 (d, J = 17.2 Hz, 2 H), 1.01 (s, 6 H), 0.87 (s, 6 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 194.4, 154.0, 151.4, 144.4, 136.0, 135.3, 124.2, 117.8, 110.3, 49.9, 39.6, 32.9, 32.1, 28.9, 26.4 ppm. ESI-HRMS: m/z calcd for C₂₃H₂₅FN₂O₄ [M + H⁺]: 412.1798; found: 412.1795. 9-(2-Bromo-4-fluorophenyl)-3,4,6,7-tetrahydro-3,3,6,6-tetramethylacridine-1,8-(2H,5H,9H,10H)-dione (7c) Yield 91%; yellow solid; mp 390–392 °C. ¹H NMR (400 MHz, CDCl₃): δ = 9.36 (s, 1 H), 7.27–7.21 (m, 2 H), 7.14 (t, J = 8.0 Hz, 1 H), 4.91 (s, 1 H), 2.27 and 2.16 (AB system, J = 17.2 Hz, 4 H), 2.08 (s, 3 H), 1.93 (d, J = 17.2 Hz, 1 H), 1.00 (s, 6 H), 0.84 (s, 6 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 195.6, 161.5, 151.3, 135.5, 133.9, 128.0, 120.2, 119.6, 114.9, 51.9, 39.2, 33.5, 32.5, 30.5, 30.2, 27.7 ppm. 9-(3-Fluoro-4-methylphenyl)-3,4,6,7-tetrahydro-3,3,6,6-tetramethylacridine-1,8-(2H,5H,9H,10H)-dione (7d) Yield 95%; yellow solid; mp 345–347 °C. ¹H NMR (400 MHz, CDCl₃): δ = 7.04 (t, J = 8.0 Hz, 1 H), 6.86–6.80 (q, 2 H), 4.77 (s, 1 H), 4.66 (s, 1 H), 2.44 and 2.34 (AB system, J = 17.2 Hz, 4 H), 2.16 (d, J = 16.1 Hz, 2 H), 2.10 (s, 3 H), 1.98 (d, J = 16.1 Hz, 2 H), 0.99 (s, 6 H), 0.86 (s, 6 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 194.3, 161.3, 159.0, 149.5, 147.2, 130.5, 123.1, 114.0, 111.0, 50.1, 38.8, 33.2, 32.1, 29.0, 26.4, 13.7 ppm. ESI-HRMS: m/z calcd for C₂₄H₂₈FNO₂ [M + H⁺]: 381.2104; found: 381.2102. 9-(2,3-Difluorophenyl)-3,4,6,7-tetrahydro-3,3,6,6-tetramethylacridine-1,8-(2H,5H,9H,10H)-dione (7e) Yield 91%; white solid; mp 167–168 °C. ¹H NMR (400 MHz, CDCl₃): δ = 7.01–6.97 (m, 2 H), 6.89 (d, J = 8.8 Hz, 1 H), 5.65 (s, 1 H), 4.74 (s, 1 H), 2.40 and 2.34 (AB system, J = 17.2 Hz, 4 H), 2.20 (d, J = 16.1 Hz, 2 H), 2.10 (d, J = 16.1 Hz, 2 H), 1.01 (s, 6 H), 0.88 (s, 6 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 189.2, 151.8, 150.2, 149.4, 128.6, 123.6, 123.0, 115.0, 114.8, 46.4, 39.2, 34.5, 31.1, 28.7, 28.0 ppm. 9-(3,5-Difluorophenyl)-3,4,6,7-tetrahydro-3,3,6,6-tetramethylacridine-1,8-(2H,5H,9H,10H)-dione (7f) Yield 92%; white solid; mp 172–174 °C. ¹H NMR (400 MHz, CDCl₃): δ = 6.64–6.58 (m, 3 H), 5.48 (s, 1 H), 4.88 (s, 1 H), 2.44–2.34 (m, 8 H), 1.22 (s, 6 H), 1.10 (s, 6 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 190.7, 164.1, 161.8, 142.8, 114.8, 110.0, 109.7, 101.6, 101.1, 46.9, 39.4, 32.8, 31.4, 29.4, 27.3 ppm. ESI-HRMS: m/z calcd for C₂₃H₂₅F₂NO₂ [M + H⁺]: 385.1853; found: 385.1857.