Synlett 2012; 23(20): 2985-2991
DOI: 10.1055/s-0032-1317670
letter
© Georg Thieme Verlag Stuttgart · New York

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
Further Information

Publication History

Received: 28 September 2012

Accepted after revision: 29 October 2012

Publication Date:
29 November 2012 (online)


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.

 
  • 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 1H 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 1H 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 1H 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 1H 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 1H 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.