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

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

› Author Affiliations

Abstract

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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

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References

References and Notes
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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.