3.2. General Procedure of the Synthesis of Chromene Analogues

Next, 100.2 g (1 mole) of 3-methyl-but-2-eneoic acid and 1319.7 g (780.1 mL, 8.6 moles) of phosphorus oxychloride were stirred for 10 min. When the reaction mixture cooled down to the 25 ± 2 °C, the flask was charged with 201.5 g (1.4 moles) of zinc chloride. To this mixture, 126.14 g (1.0 mole) of 1,2,3-trihydroxybenzenes 1a and 1,2,4-trihydroxybenzenes 1b was added. Then, the reaction mixture was stirred at 25 °C for 6 h to yield 3a (1-[2′,3′,4′-trihydroxyphenyl]-3-methyl-1-oxo-buta-2-ene) and stirred for 2 h to yield 3b (1-[2′,4′,5′-trihydroxyphenyl]-3-methyl-1-Oxo-but-2-ene). Compound 8 (1-(2′,4′-dihydroxyphenyl)-3-methyl-1-oxo-buta-2-ene) was synthesized by mixing 55.06 g (0.5 moles) of resorcinol (1,3-dihydroxybenzene), 50.10 g (0.5 moles) of 3-methyl-but-2-enoic acid, and 613.8 g (363.2 mL, 4 moles) of POCl₃ at 25 °C under inert gas (argon) conditions, and then 80 g (0.6 moles) of dry AlCl₃ was added to it to yield 8 [65]. The reaction was monitored by TLC (n-hexane: ethyl acetate 1:1); upon completion, the mixture was poured onto crushed ice and then filtered. The crude solid dried under reduced pressure and the product was obtained by re-crystallization from the ethanol–water (95:5) system to yield 3a, 3b, and 8, respectively. The reaction yield was calculated as a percentage of the actual weight of purified 3a (68.62%), 3b (50.85%), and 8 (97.4%) to their theoretical weight. The measured melting point (MP) was 137–138 °C for 3a and 165 °C for 3b (the reported MP was 162–164 °C [33]), the while MP of 8 was 74 °C. Purified compounds were subjected to structure elucidation; the GC-MS spectral data for compound 3a, R_t = 20.271 min, MS (EI, 70 eV): m/z (%) = 208 (54) [M⁺], 193 (100) [M-Me], 152 (81), 137 (15), 123 (21), 113 (19), 106 (21), 95 (26), 83 (26), 77 (30), 68 (30), 51 (54).

The ¹HNMR (DMSO-d6) spectral data for compound 3a: 2.0 [s, 3H, CH₃), 2.15 (s, 3H, CH₃), 6.36 [duplet (d)], 1H, J = 9.4 Hz, 5′-H), 6.90 (s, 1H, 2-H), 7.37 (d, 1H, J = 9.4 Hz, 6′-H), 8.6 (s, 1H, 3′OH), 10.5 (s, 1H, 4′OH), 13.29 (s, 1H, 2′OH).

The ¹HNMR (DMSO-d6) spectral data for compound 3b: 2.0 (s, 3H, CH₃), 2.11 (s, 3H, CH₃), 6.28 (s, 1H, 3′H), 6.76 (s, 1H, 2H), 7.23 (s, 1H, 6′H), 8.75 (broad, 1H, 4′/5′OH), 10.39 (broad, 1H, 4′/5′OH), 12.85 (s, 1H, 2′OH).

The GC-MS spectral data for compound 8: R_t = 17.370 min, MS (EI, 70 eV): m/z (%) = 192 (5) [M+], 177 (100) [M⁺-Me], 137 (31), 108 (7), 81 (11), 69 (11), 51 (16).

The ¹HNMR (DMSO-d6) spectral data for compound 8: 2.01 (s, 3H, CH₃), 2.15 (s, 3H, CH₃), 6.25 (s, 1H, H-3′), 6.35 (d, 1H, J = 9 Hz, H-5′), 6.91 (s, 1H, H-2), 7.84 (d, 1H, J = 9 Hz, H-6′), 10.57 (s, 1H, OH-4′), 13.26 (s, 1H, OH-2′).

The ¹HNMR, ¹³CNMR, and mass spectra of all prepared compounds in the experimental section are available in the Supplementary Figures S3–S65.

Afterwards, 100 g (0.48 moles) of 3a or 3b compounds or 76.8 g (0.4 moles) of compound 8 was dissolved in 1 L of 5% aqueous NaOH solution (1.25M) and stirred for 1.5–2.0 h at room temperature. After the reaction was completed, the solution was diluted with 500 mL of cold distilled water. Then, the solution was acidified by dropping 36% HCl until pH 1 was obtained. The 4c (5,7-dihydroxy-2,2-dimethyl-4-chroman-4-one) was prepared directly from 1,3,5-trihydroxybenzene (1c), and 162.14g (1.0 mole) of 3-methyl-but-2-eneoic acid and POCl₃/ZnCl₂ were mixed. The reaction was set overnight at 25 °C, as described in Section 2.1. The purification of crude products was achieved by column chromatography to obtain 4a and re-crystallization from ethanol–water (9:1) to obtain 4b, 4c, and 8. The reaction yields 95.1%, 87.6%, 51.8%, and 74.2% and MPs were 197–198, 207, 142, and 173 °C for 4a, 4b, 4c, and 8, respectively (reported MPs were 199, 208, and 142 °C for 4a–c, respectively, [66]). The GC-MS spectral data of relevant compound 4a (7,8-dihydroxy 2,2-dimethyl chroman-4-one), R_t = 19.763 min, MS (EI, 70 eV): m/z (%) = 208 (39) [M⁺], 193 (40.5), 152 (100) [M⁺-CH₂=C(CH₃)₂], 124 (13.4), 106 (14.1), 113 (19), 106 (14), 95 (8), 68 (11), 53 (13).

The ¹HNMR (DMSO-d6) spectral data for compound 4a: 1.39 (s, 6H, 2CH₃), 2.66 (s, 2H, CH₂), 6.45 (d, 1H, J = 6.8 Hz, H-6), 7.11 (d, 1H, J = 6.8 Hz, H-5), 8.48 (broad, 1H, OH-8), 9.97 (s, 1H, OH-7).

The GC-MS spectral data for compound 4b (6,7-dihydroxy2,2-dimethylchroman-4-one), R_t = 21.313 min, MS (EI, 70 eV): m/z (%) = 208 (48) [M⁺], 193 (100) [M⁺-Me], 153 (27), 124 (41), 106 (14.1), 96 (20), 78 (11), 51 (13).

The ¹HNMR (DMSO-d6) spectral data for compound 4b: 1.34 (s, 6H, 2CH₃), 2.59 (s, 2H, CH₂), 6.27 (s, 1H, H-8), 7.04 (s, 1H, H-5), 9.04 (broad, 1H, OH-6), 10.14 (broad, 1H, OH-7).

The GC-MS spectral data for compound 4c (5,7-dihydroxy-2,2-dimethyl chroman-4-one), R_t = 19.790 min, MS (EI, 70 eV): m/z (%) = 207 (100) [M+], 167 (78), 138 (39), 123 (15), 110 (17), 69 (38), 51 (15).

The ¹HNMR (DMSO-d6) spectral data for compound 4c: 1.38 (s, 6H, 2CH₃), 2.77 (s, 2H, CH₂), 5.82 (multiplet [m], 2H, ArH 6/8), 10.73 (s, 1H, OH-5), 12.11 (s, 1H, OH-7).

The GC-MS spectral data for compound 9: 7-hydroxy 2, 2-dimethyl chroman-4-one, R_t = 16.521 min, MS (EI, 70 eV): m/z (%) = 192 (55) [M+], 177 (100) [M⁺-Me], 137 (61), 108 (56), 95 (5), 80 (20), 69 (18), 51 (21).

The ¹HNMR (CDCl₃) of compound 8 had the following attributes; 1.46 (s, 6H, 2CH3), 2.68 (s, 2H, CH₂), 5.81 (broad, 1H, OH-7), 6.35 (s, 1H, ArH-8), 6.48 (d, 1H, J = 9 Hz, ArH-6), 7.80 (d, 1H, J = 9 Hz, ArH-5).

A regioselective alkylation was used to prepare the monoalkoxy and monohydroxy 2,2-dimethylchroman-4-one series (5a–f). Under inert gas (argon) conditions, 40 g (0.19 moles) of 4a–c or 19.2 g (0.1 moles) of compound 9 was charged with 100 mL of dry N,N-dimethylformamide for 4a–c or 100 of dry acetone for compound 9, and then 26.6 g (0.19 moles) or 14.0 g (0.1 moles) of anhydrous K₂CO₃ was added to the solutions and stirred at 25 °C for 1h. The resultant solution was refluxed at 80 °C. Then, 29.81 g (19.47 mL, 0.21 moles) of 99% methyl iodide used to yield 5a–c and 15.61 g (10.20 mL, 0.11 moles) used to prepare 10a, or 32.76 g (16.8 mL, 0.21 moles) of 99% ethyl iodide used to yield 5d–f and 17.16 g (8.80 mL, 0.11 moles) used to yield 10b, was dropped by a programable syringe pump (LAMBDA-FIT, Baar, Switzerland) for over 1.5–6.0 h. The progress of the reaction was monitored by TLC (9:1 hexane: ethylacetate). The reaction times for individual compounds are listed in Table 3.

The reaction time and % of reaction yield of the synthesis of monoalkoxy, monohydroxy 2,2-dimethylchroman-4-ones (5a–f), dialkoxy, 2,2-dimethylchroman-4-ones (6a–f), and monoalkoxy, 2,2-dimethylchroman-4-ones (10a–b).

* Reaction yield= [actual yield (of purified compound)/theoretical yield] × 100.

After completing the reaction, the mixture was cooled to 22 °C ± 2 and the solvent was distilled off. Then, the residue was dissolved in a 5% aqueous NaOH solution and extracted with CH₂Cl₂. The organic phase was discarded, and the alkaline aqueous phase was then acidified with conc. HCl (pH 1–2). The filtered-out solid was dried overnight under reduced pressure. The product was subjected to re-crystallization using an ethanol–water (5% water) extraction. The recorded MPs were 78, 108, 54, 141–143, 106–107, and 74 °C for 5a–f, respectively, while the reported MPs were 70, 113–114, 68, 141, 109, and 78 °C, respectively [66,67,68]. The recorded MPs for 10a and 10b were 79–81 and 85 °C, respectively.

The GC-MS spectral data for compound 5a (7-methoxy, 8-hydroxy 2,2-dimethyl chroman-4-one): R_t = 21.123 min, MS (EI, 70 eV): m/z (%) = 222 (80) [M+], 167 (100) [M⁺-CH=C(CH₃)₂], 207 (90), 192 (8.9), 152 (7.1), 148 (75), 137 (28), 120 (91), 95 (51), 67 (22), 53 (31).

The ¹HNMR (CDCl₃) spectral data for compound 5a: 1.51 (s, 6H, 2CH₃), 2.72 (s, 2H, CH₂), 3.96 (s,3H, OCH₃-7), 5.42 (broad, 1H, OH-8), 6.6 (d, 1H, J = 9.8 Hz, ArH-6), 7.5 (d, 1H, J = 9.8 Hz, ArH-5).

The GC-MS spectral data for compound 5b (7-methoxy, 6-hydroxy 2,2-dimethyl chroman-4-one): R_t = 22.062 min, MS (EI, 70 eV): m/z (%) = 222 (50) [M+], 167 (100) [M⁺-CH=C(CH₃)₂], 207 (99), 192 (10), 138 (8), 123 (71), 111 (9), 95 (16), 79 (9), 53 (51).

The ¹HNMR (CDCl₃) spectral data for compound 5b: 1.45 (s, 6H, 2CH₃), 2.67 (s, 2H, CH₂), 3.93 (s, 3H, OCH₃-7), 5.30 (s, 1H, OH-6), 6.41 (s, 1H, ArH-8), 7.36 (s,1H, ArH-5).

The GC-MS spectral data for compound 5c (7-methoxy, 5-hydroxy 2,2-dimethyl chroman-4-one): R_t = 19.920 min, MS (EI, 70 eV): m/z (%) = 222 (46) [M+], 207 (100) [M⁺-Me], 166 (24), 138 (24), 123 (6), 110 (13), 95 (32), 69 (25), 53 (14).

The ¹HNMR (CDCl₃) spectral data for compound 5c: 1.49 (s, 6H, 2CH₃), 2.72 (s, 2H, CH₂), 3.84 (s, 3H, OCH₃-7), 5.9 (d, 1H, J = 2.4 Hz, H-6/8), 6.3 (d, 1H, J = 2.4 Hz, H-6/8), 12.05 (s, 1H, OH-5).

The GC-MS spectral data for compound 5d (7-ethoxy, 8-hydroxy 2,2-dimethyl chroman-4-one): R_t = 21.871 min, MS (EI, 70 eV): m/z (%) = 236 (81) [M+], 152 (100) [M⁺-C₄H₁₀O], 221 (81), 193 (26), 181 (76), 162 (52), 134 (44), 123 (42), 106 (26), 95 (42), 79 (25), 68 (27), 53 (25). The ¹HNMR (CDCl₃) spectral data for compound 5d: 1.52 (triplet (t), 3H, J = 7.3 Hz, OCH2CH₃), 1.57 (s, 6H, 2CH₃), 2.77 (s, 2H, CH₂), 4.25 (quartet (q), 2H, J = 7.3 Hz, OCH₂CH₃), 5.49 (broad, 1H, OH-8), 6.63 (d, 1H, J = 9.8 Hz, ArH-6), 7.5 (d, 1H, J = 9.8 Hz, H-5).

The GC-MS spectral data for compound 5e (7-ethoxy, 6-hydroxy 2,2-dimethyl chroman-4-one): R_t = 23.031 min, MS (EI, 70 eV): m/z (%) = 236 (57) [M+], 221 (100) [M⁺-Me], 193 (47), 180 (56), 153 (55), 124 (14), 107 (10), 95 (12), 82 (35), 53 (48).

The ¹HNMR (CDCl₃) spectral data for compound 5e: 1.45 (s, 6H, 2CH₃), 1.49 (triplet [t], 3H, J = 7.3 Hz, OCH₂CH₃), 2.66 (s, 2H, CH₂), 4.13 (q, 2H, J = 7.3 Hz, OCH₂CH₃), 5.3 (s, 1H, OH-6), 6.38 (s, 1H, ArH-8), 7.36 (s, 1H, ArH-5).

The GC-MS spectral data for compound 5f (7-ethoxy, 5-hydroxy 2,2-dimethyl chroman-4-one): R_t = 20.623 min, MS (EI, 70 eV): m/z (%) = 236 (58) [M+], 221 (100) [M⁺-Me], 193 (49), 181 (50), 153 (45), 124 (49), 96 (19), 69 (46), 55 (17).

The ¹HNMR (CDCl₃) spectral data for compound 5f: 1.4 (t, 3H, J = 7.3 Hz, OCH₂CH₃), 1.5 (s, 6H, 2CH₃), 2.68 (s, 2H, CH₂), 4.02 (q, 2H, J = 7.3 Hz, OCH₂CH₃), 5.93 (d, 1H, J = 2.4 Hz, ArH 6/8), 5.99 (d,1H, J = 2.4 Hz, ArH 6/8), 12.01 (s,1H, OH-5).

The GC-MS spectral data for compound 10a (7-O-methyl-2, 2-dimethyl chroman-4-one) R_t = 15.119 min, MS (EI, 70 eV): m/z (%) = 206 (31) [M+], 191 (100) [M⁺-Me], 151 (80), 122 (50), 107 (30), 95 (11), 79 (28), 63 (25), 51 (29).

The ¹HNMR (CDCl₃) spectral data for compound 10a: 1.46 (s, 6H, 2CH₃), 2.68 (s, 2H, CH₂), 3.84 (s, 3H, OCH₃), 6.38 (m, 1H, ArH-8), 6.54 (d, 1H, J = 9 Hz, ArH-6), 7.8 (d, 1H, J = 9 Hz, ArH-5).

The GC-MS spectral data for compound 10b (7-O-ethyl-2, 2-dimethyl chroman-4-one): R_t = 15.991 min, MS (EI, 70 eV): m/z (%) = 220 (67) [M+], 205 (100) [M⁺-Me], 165 (49), 136 (69), 108 (49), 80 (17), 69 (18), 51 (20).

The ¹HNMR (CDCl₃) spectral data for compound 10b: 1.42 (t, 3H, J = 6.0 Hz, OCH₂CH₃), 1.45 (s, 6H, 2CH₃), 2.66 (s, 2H, CH₂), 4.05 (q, 2H, J = 6.0 Hz, OCH₂CH₃), 6.35 (m, 1H, ArH-8), 6.52 (d, 1H, J = 9 Hz, ArH-6), 7.78 (d, 1H, J = 9 Hz, ArH-5).

To obtain 6a–f, 0.1 moles of respective 5a–f in 100 mL of N,N-dimethylformamide was treated with 15.4g (0.11 moles) of anhydrous K₂CO₃, and 19.87 g (12.98 mL, 0.14 moles) of CH₃I (99%) was added using a programmable syringe pump (LAMBDA-FIT, Switzerland), as described in Section 2.2. The reaction time and reaction yield are presented in Table 3. The products were refined after cooling to 20 °C, and then the mix was poured onto crushed ice and extracted twice with CH₂Cl_2. The organic layer was washed two times with NaOH 2% and water, and dried over anhydrous sodium sulfate. After removing the solvent, the product was re-crystallized from ethanol. The GC-MS spectral data for compound 6a (7,8-dimethoxy-2,2-dimethylchroman-4-one): R_t = 20.227 min, MS (EI, 70 eV): m/z (%) = 236 (85) [M+], 221 (100) [M⁺-Me], 181 (93), 152 (89), 137 (51), 120 (33), 109 (34), 94 (34), 78 (17), 66 (31), 53 (34), 51 (12).

The ¹HNMR (CDCl₃) spectral data for compound 6a: 1.52 (s, 6H, 2CH₃), 2.71 (s, 2H, CH₂), 3.8 (s, 3H, OCH₃), 3.9 (s, 3H, OCH₃), 6.6 (d, 1H, J = 10.6 Hz, ArH-6), 7.66 (d, 1H, J = 10.6 Hz, ArH-5).

The GC-MS spectral data for compound 6b (6,7-dimethoxy-2,2-dimethylchroman-4-one): R_t = 17.603 min, MS (EI, 70 eV): m/z (%) = 236 (49) [M+], 221 (100) [M⁺-Me], 205 (5), 181 (79), 165 (32), 137 (33), 109 (10), 109 (10), 53 (37).

The ¹HNMR (CDCl₃) spectral data for compound 6b: 1.47 (s, 6H, 2CH₃), 2.68 (s, 2H, CH₂), 3.89 (s, 3H, OCH₃), 3.89 (s, 3H, OCH₃), 6.41 (s, 1H, ArH-8), 7.27 (s, 1H, ArH-5).

The GC-MS spectral data for compound 6c (5,7-dimethoxy-2,2-dimethylchroman-4-one): R_t = 18.097 min, MS (EI, 70 eV): m/z (%) = 236 (54) [M+], 180 (100) [M⁺-CH₂=C(CH₃)₂], 221 (25), 152 (59), 137 (62), 109 (20), 95 (18), 79 (16), 53 (25).

The ¹HNMR (CDCl₃) spectral data for compound 6c: 1.44 (s, 6H, 2CH₃), 2.64 (s, 2H, CH₂), 3.82 (s, 3H, OCH₃), 3.88 (s, 3H, OCH₃), 6.03 (s, 2H, ArH-6/8).

The GC-MS spectral data for compound 6d (7-ethoxy- 8-methoxy-2,2-dimethyl chroman-4-one): R_t = 19.256 min, MS (EI, 70 eV): m/z (%) = 250 (2.6) [M+], 219 (100) [M⁺-OCH₃], 234 (12), 191 (77), 176 (12), 147 (6), 69 (17), 53 (5).

The ¹HNMR (CDCl₃) spectral data for compound 6d: 1.44 (t, 3H, J = 7.8 Hz, OCH₂CH₃), 1.49 (s, 6H, 2CH₃), 2.68 (s, 2H, CH₂), 3.84 (s, 3H, OCH₃-8), 4.1 (q, 2H, J = 7.8 Hz, OCH₂CH₃), 6.56 (d, 1H, J = 10.6 Hz, ArH-6), 7.61 (d, 1H, J = 10.6 Hz, ArH-5).

The GC-MS spectral data for compound 6e (7-ethoxy- 6-methoxy-2,2-dimethyl chroman-4-one): R_t = 22.209 min, MS (EI, 70 eV): m/z (%) = 250 (2.6) [M+], 235 (100) [M⁺-Me], 195 (76), 179 (8), 167 (72), 137 (20), 123 (20), 111 (6), 95 (16), 69 (78), 53 (5).

The ¹HNMR (CDCl₃) spectral data for compound 6e: 1.46 (s, 6H, 2CH₃), 1.55 (t, 3H, J 7.4 Hz, OCH₂CH₃), 2.66 (s, 2H, CH₂), 3.87 (s, 3H, OCH₃-6), 4.13 (q, 2H, J = 7.4 Hz, OCH₂CH₃), 6.39 (s, 2H, ArH-5/8).

The GC-MS spectral data for compound 6f (7-ethoxy- 5-methoxy-2,2-dimethyl chroman-4-one): R_t = 22.962 min, MS (EI, 70 eV): m/z (%) = 250 (51) [M+], 166 (100) [M⁺-C₅H₈O], 150 (24), 138 (27), 123 (24), 69 (36).

The ¹HNMR (CDCl₃) spectral data for compound 6f: 1.39 (t, 3H, J = 7.8 Hz, OCH₂CH₃), 1.44 (s, 6H, 2CH₃), 2.64 (s, 2H, CH₂), 3.87 (s, 3H, OCH₃-5), 4.03 (q, 2H, J = 7.8 Hz, OCH₂CH₃), 6.01 (m, 2H, ArH-6/8).

The 2H-1-chromene compounds (7a–f) were prepared following the reduction and dehydration of the corresponding 6a–f compounds. In total, 0.05 moles of compounds 6a–f was dissolved in 100 mL of dry methanol (absolute) and then treated with 5 g (0.13 moles) of NaBH₄ dissolved in 50 mL of dry methanol (absolute) using a dropping funnel over one hour under a stream of argon gas condition. Similarly, 7-O-methyl-2,2-dimethylchromene (11a; precocenes I) and 7-O-ethyl-2,2-dimethylchromene (11b) were synthesized by reducing 0.07 moles of compounds 10a–b, respectively, with 5.31 g (0.13 moles) of LiAlH₄ in 50 mL of dry tetrahydrofuran (THF). After the reduction process, the reaction was stopped by adding 100 mL of water, and the product was extracted from the mixture with CH₂Cl₂. The reaction was monitored by TLC with hexane–ethyl acetate in a ratio of 1:1. Subsequently, the solvent was removed, and the residue was subjected to dehydration with 100 mL (4 mol × L⁻¹) of HCl in dry THF at 5 °C using a dropping funnel over 1h. The time required to complete the reduction and dehydration is presented in Table 4. The crude products were extracted by diethyl ether several times, and the combined organic layer was extracted with 5% NaOH solution and then dried over anhydrous Na₂SO₄. The product was obtained by column chromatography (9:1 hexane: Et₂O).

Reaction times required for reduction and dehydration of corresponding compounds (6a–f) and (11a–b), as well as the % reaction yields.

* The reaction yield was calculated over the actual yield of the final step.

The GC-MS spectral data for compound 7a (7,8-dimethoxy 2,2-dimethyl 2H-chromene): R_t = 17.348 min, MS (EI, 70 eV): m/z (%) = 220 (16) [M+], 205 (100) [M⁺-Me], 190 (14), 161 (14), 144 (7), 91 (7), 51 (6).

The ¹HNMR (CDCl₃) spectral data for compound 7a: 1.47 (s,6H,2CH₃), 3.84 (s, 3H, OCH₃), 3.87 (s, 3H, OCH₃), 5.5 (d, 1H, J = 9.9 Hz, H-3), 6.26 (d, 1H, J = 9.9 Hz, H-4), 6.41 (d, 1H, J = 7.8 Hz, ArH-6), 6.68 (d, 1H, J = 7.8 Hz, ArH-5).

The ¹³CNMR (CDCl₃) spectral data for compound 7a: 28.1 (2CH₃), 60.9 (OCH₃-7), 64.6 (OCH₃-8), 76.5 (C-2), 105.5 (C-6), 116.3 (C-4a), 120.8 (C-5), 122.3 (C-4), 128.6 (C-3), 138.1 (C-8), 146.7 (C-8a), 152.98 (C-6).

The GC-MS spectral data for compound 7b (6,7- dimethoxy 2,2-dimethyl 2H-chromene): R_t = 17.781 min, MS (EI, 70 eV): m/z (%) = 220 (16) [M+], 205 (100) [M⁺-Me], 189 (13), 161 (15), 91 (10), 77 (10), 69 (11), 51 (6).

The ¹HNMR (CDCl₃) spectral data for compound 7b: 1.41 (s, 6H, 2CH₃), 3.84 (s, 3H, OCH₃), 3.85 (s, 3H, OCH₃), 5.46 (d, 1H, J = 9.9 Hz, H-3), 6.24 (d, 1H, J = 9.9 Hz, H-4), 6.43 (s, 1H, ArH-8), 6.254 (s, 1H, ArH-5).

The ¹³CNMR (CDCl₃) spectral data for compound 7b: 27.9 (2CH3), 56.1 (OCH₃-6/7), 56.7 (OCH₃-6/7), 76.8 (C-2), 101.2 (C-8), 109.9 (C-5), 113.2 (C-4a), 122.1 (C-4), 128.4 (C-3), 143.2 (C-8a), 147.3 (C-7), 149.8 (C-6).

The GC-MS spectral data for compound 7c (5,7-dimethoxy 2,2-dimethyl 2H-chromene): R_t = 18.287 min, MS (EI, 70 eV): m/z (%) = 220 (14) [M+], 205 (100) [M⁺-Me], 190 (18), 161 (11), 147 (8), 77 (8), 69 (8), 51 (4).

The ¹HNMR (CDCl₃) spectral data for compound 7c: 1.41 (s, 6H, 2CH₃), 3.76 (s, 3H, OCH₃), 3.78 (s, 3H, OCH₃), 5.40 (d, 1H, J = 10.3 Hz, H-3), 6.01 (m, 2H, ArH-6/8), 6.57 (d, 1H, J = 10.3 Hz, H-4).

The ¹³CNMR (CDCl₃) spectral data for compound 7c: 27.7 (2CH₃), 55.2 (OCH₃-5/7), 55.4 (OCH₃-5/7), 76.1 (C-2), 91.4 (C-6), 94.1 (C-8), 104.2 (C-4a), 116.7 (C-4), 125.7 (C-3), 154.7 (C-8a), 156.1 (C-7), 161.01 (C-5).

The GC-MS spectral data for compound 7d (7-ethoxy-8-methoxy 2,2-dimethyl 2H-chromene): R_t = 18.041 min, MS (EI, 70 eV): m/z (%) = 236 (25) [M+], 219 (100) [M⁺-Me], 191 (51), 176 (37), 115 (10), 91 (20), 77 (12), 51 (10).

The ¹HNMR (CDCl₃) spectral data for compound 7d: 1.41 (t, 3H, J = 6.9 Hz, OCH₂CH₃), 1.74 (s, 6H, 2CH₃), 3.86 (s, 3H, OCH₃), 4.06 (q, 2H, J = 6.9 Hz, OCH₂CH₃), 5.51 (d, 1H, J = 9.5 Hz, H-3), 6.28 (d, 1H, J = 9.5 Hz, H-4), 6.41 (d, 1H, J = 8.6 Hz, ArH-6), 6.65 (d, 1H, J = 8.6 Hz, ArH-5).

The ¹³CNMR (CDCl₃) spectral data for compound 7d: 15.4 (OCH₂CH₃), 28.41 (2CH3), 61.23 (OCH₃), 64.94 (OCH₂CH₃), 76.77 (C-2), 105.85 (C-6), 116.65 (C-4a), 121.14 (C-5), 122.56 (C-4), 128.93 (C-3), 138.93 (C-8), 147.3 (C-8a), 153.29 (C-7).

The GC-MS spectral data for compound 7e (7-ethoxy-6-methoxy 2,2-dimethyl 2H-chromene): R_t = 18.826 min, MS (EI, 70 eV): m/z (%) = 236 (25) [M+], 219 (100) [M⁺-Me], 191 (91), 176 (24), 91 (22), 77 (20), 69 (23), 51 (12).

The ¹HNMR (CDCl₃) spectral data for compound 7e: 1.42 (s, 6H, 2CH₃), 1.48 (t, 3H, J = 6.9 Hz, OCH₂CH₃), 3.8 (s, 3H, OCH₃), 4.06 (q, 2H, J = 6.9 Hz, OCH₂CH₃), 5.45 (d, 1H, J = 10 Hz, H-3), 6.24 (d, 1H, J = 10 Hz, H-4), 6.42 (s, 1H, ArH-5/8), 6.54 (s, 1H, ArH-5/8).

The ¹³CNMR (CDCl₃) spectral data for compound 7e: 14.9 (OCH₂CH₃), 27.8 (2CH₃), 56.8 (OCH₃), 64.4 (OCH₂CH₃), 76.8 (C-2), 102.3 (C-8), 110.3 (C-4a), 113.3 (C-5), 122.2 (C-4), 128.4 (C-3), 143.1 (C-8a), 147.4 (C-7), 149.5 (C-6).

The GC-MS spectral data for compound 7f (7-ethoxy-5-methoxy 2,2-dimethyl 2H-chromene): R_t = 16.081 min, MS (EI, 70 eV): m/z (%) = 236 (2) [M+], 219 (100) [M⁺-Me], 234 (20), 191 (66), 176 (24), 147 (19), 91 (17), 69 (22), 51 (10).

The ¹HNMR (CDCl₃) spectral data for compound 7f: 1.38 (t, 3H, J = 6.8 Hz, OCH₂CH₃), 1.41 (s, 6H,2CH₃), 3.79 (s,3H, OCH₃), 4.0 (q, 2H, J = 6.8 Hz, OCH₂CH₃), 5.41 (d, 1H, J = 9.8 Hz, H-3), 6.02 (m, 2H, ArH-6/8), 6.58 (d, 1H, J = 9.8 Hz, H-4).

The ¹³CNMR (CDCl₃) spectral data for compound 7f: 14.8 (OCH₂CH₃), 28.1 (2CH₃), 55.4 (OCH₃), 63.0 (OCH₂CH₃), 76.59 (C-2), 92.11 (C-6), 94.82 (C-8), 104.53 (C-4a), 116.79 (C-4), 126.17 (C-3), 155.01 (C-8a), 158.65 (C-7), 160.76 (C-5).

The GC-MS spectral data for compound 11a (7-O-methyl-2,2-dimethylchromene): R_t = 12.582 min, MS (EI, 70 eV): m/z (%) = 190 (10) [M+], 175 (100) [M⁺-Me], 160 (10), 132 (14), 115 (4), 103 (4), 91 (4), 77 (8), 63 (6), 51 (8).

The ¹HNMR (CDCl₃) spectral data for compound 11a: 1.41 (s, 6H, 2CH₃), 3.75 (s, 3H, OCH₃), 5.45 (d, 1H, J = 10 Hz, H-3), 6.26 (d, 1H, J = 10 Hz, H-4), 6.36 (m, 1H, ArH-8), 6.4 (d, 1H, J = 8.0 Hz, ArH-6), 6.86 (d, 1H, J = 8.0 Hz, ArH-5).

The ¹³CNMR (CDCl₃) spectral data for compound 11a: 28.02 (2CH₃), 55.1 (OCH₃), 76.7 (C-2), 102.09 (C-8), 106.8 (C-4a), 115.03 (C-5), 122.02 (C-4), 127.3 (C-3), 128.5 (C-6), 154.5 (C-8a), 161.06 (C-7).

The GC-MS spectral data for compound 11b (7-O-ethyl-2,2-dimethylchromene): R_t = 13.432 min, MS (EI, 70 eV): m/z (%) = 204 (20) [M+], 161 (100) [M⁺-C₂H₄O], 189 (92), 132 (11), 115 (9), 105 (7), 91 (7), 77 (21), 63 (7), 51 (8).

The ¹HNMR (CDCl₃) spectral data for compound 11b: 1.37 (t, 3H, J = 6.0 Hz, OCH₂CH₃), 1.42 (s, 6H, 2CH₃), 4.01 (q, 2H, J = 6.0 Hz, OCH₂CH₃), 5.45 (d, 1H, J = 10 Hz, H-3), 6.26 (d, 1H, J = 10 Hz, H-4), 6.36 (m, 1H, ArH-8), 6.4 (d, 1H, J = 8.0 Hz, ArH-6), 6.86 (d, 1H, J = 8.0 Hz, ArH-5).

The ¹³CNMR (CDCl₃) spectral data for compound 11b: 15.2 (OCH₂CH₃), 28.4 (2CH₃), 63.8 (OCH₂CH₃), 76.7 (C-2), 102.9 (C-8), 107.6 (C-4a), 114.9 (C-5), 122.3 (C-4), 127.3 (C-3), 128.1 (C-6), 154.5 (C-8a), 160.4 (C-7).

The antifungal activity of all synthesized compounds and the standard antifungal drug amphotericin-B was evaluated in vitro against two phytopathogenic fungi, R. solani and A. niger, using the poisoned food technique [69]. Pure fungi cultures were obtained from the Department of Plant Pathology, Faculty of Agriculture, Ain-Shams University, Egypt, and the Department of Biology, Faculty of Science, Memorial University of Newfoundland, St. John’s, NL. Canada. Two cultural media, Czapek–Dox agar (CDA) and potato dextrose agar (PDA), were used in this study. Cultural media were obtained from Merck Chem. Co (Canada). CDA media were used as specific growth media for A. niger, while PDA media were used as growth media for R. solani. The fungitoxic activity of 29 compounds (chromanones and chromenes) was tested against A. niger and R. solani in vitro at various concentrations, ranging from 100 to 800 μg × mL⁻¹, while amphotericin-B (X-GEN, NY, USA) was used at 5–25 μg × mL⁻¹. An in vitro assay was performed on PDA and CDA growth media treated with gradient concentrations of all the synthesized compounds (100–800 µg × mL⁻¹ in sterilized DMSO (5%) + Tween-20 as a dispersing agent). Then, 1 mL of a solution containing different compounds was poured into sterilized melted media, homogenized, and plated into Petri dishes (90 × 15 mm). The media-containing compounds were incubated for 48 h at 25 °C. After incubation, all plates were inoculated with agar plugs containing fungi and incubated again at 22 °C for 8 days. To assess mycelial inhibition, fungal growth diameters (mm) were measured daily, and radial inhibition was calculated when negative control plates were fully covered with the fungal mycelial. For all treatments, four replicates were used, and the percentage of mycelial growth inhibition was calculated according to the equation suggested by Pandey et al. [70].

where:

The positive control (inoculated media with fungus and DMSO + Tween-20) was used to evaluate the toxicity of the solvent and the dispersing agent. In addition, the synthetic antibiotic drug, amphotericin-B (X-GEN, NY, USA), was also used as a standard antifungal drug at concentrations of 5–25 µg × mL⁻¹. The EC₅₀ and EC₉₀ for all treatments were calculated using a regression equation between the log concentrations and the probit of the percentage growth inhibition of fungi, according to Abd El-Naeem et al. [71].