The Journal of Organic Chemistry
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4.2.8. 1-(3-Methoxy-4-(methoxymethoxy)phenyl)hexa-1,4-diyn-
3-one, 20. MnO2 (9.49 g, 0.109 mol, 20 equiv) was added into a
solution of 1-(3-methoxy-4-(methoxymethoxy)-phenyl)-propiolalde-
hyde 15 (1.41 g, 5.43 mmol) in dry DCM (50 mL). The mixture was
stirred overnight at room temperature (CCM, SiO2, and cyclohexane/
EtOAc, 4:1). The reaction mixture was then filtered on a short pad of
silica gel eluted with DCM, and the resulting filtrate was concentrated
and purified by chromatography (SiO2 and cyclohexane/EtOAc,
85:25) to give diynone 20 as a brown oil (1.36 g, 97%). Rf: 0.31
(cyclohexane/EtOAc, 4:1). IR (KBr): 2181, 1616 (CO). 1H NMR
(400 MHz, CDCl3): δ 7.23 (dd, JH,H = 8.4, 1.9 Hz, 1H; Ar-H), 7.14
(d, JH,H = 8.4 Hz, 1H; Ar-H), 7.12 (d, JH,H = 1.8 Hz, 1H; Ar-H), 5.28
(s, 2H; OCH2O), 3.89 (s, 3H; OCH3), 3.51 (s, 3H; OCH3), 2.10 (s,
3H; CH3). 13C{1H} NMR (100 MHz, CDCl3): δ 161.0, 149.7, 149.5,
127.8, 116.0, 115.7, 112.8, 95.3, 91.6, 91.4, 89.3, 81.6, 56.6, 56.2, 4.5.
ESI-MS (HR) m/z: [M + H]+ calcd for C15H15O4, 259.0965; found,
259.0979; m/z: [M + Na]+ calcd for C15H14NaO4, 281.0784; found,
281.0807.
temperature. Then, the mixture was warmed to 40 °C with a heating
mantle and stirred for 48 h (CCM, SiO2, and EtOAc). The reaction
was quenched with water (10 mL), and the crude product was
extracted with DCM (4 × 10 mL). The combined organic phases
were washed with water (3 × 10 mL) and brine (3 × 10 mL) and
then dried over Na2SO4 and filtered. The concentrated filtrate was
purified by column chromatography (SiO2 and EtOAc) to give title
compound 22 as a yellow solid (310 mg, 38%). Rf: 0.28 (EtOAc). mp
131 °C. IR (ATR, cm−1): 3076, 2932, 1645, 1628, 1599, 1504. UV−
Vis (DMSO): 356 nm. 1H NMR (400 MHz, CDCl3): δ 7.46 (dd, JH,H
= 8.5, 2.0 Hz, 1H; Ar-H), 7.42 (d, JH,H = 16.0 Hz, 1H; Hβ), 7.31 (d,
J
J
H,H = 1.6 Hz, 1H; Ar-H), 7.30 (d, JH,H = 8.4 Hz, 1H; Ar-H), 7.19 (d,
H,H = 8.1 Hz, 1H; Ar-H), 7.09 (m, 2H; Ar-H), 6.70 (d, JH,H = 1.9 Hz,
1H; Hpyrone), 6.67 (d, JH,H = 16.0 Hz, 1H; Hα), 6.31 (d, JH,H = 1.8 Hz,
1H; Hpyrone), 5.32 (s, 2H; OCH2O), 5.28 (s, 2H; OCH2O), 3.98 (s,
3H; OCH3), 3.97 (s, 3H; OCH3), 3.54 (s, 3H; OCH3), 3.53 (s, 3H;
OCH3). 13C{1H} NMR (100 MHz, CDCl3): δ 180.3, 162.8, 161.8,
150.1, 150.0, 149.4, 148.3, 135.8, 129.4, 125.6, 121.7, 119.5, 118.3,
116.1, 116.0, 113.5, 110.5, 109.9, 109.3, 95.3, 95.2, 56.4, 56.1. ESI-MS
(HR) m/z: [M + H]+ calcd for C25H27O8, 455.1700; found,
455.1696; m/z: [M + Na]+ calcd for C25H26NaO8, 477.1520;
found, 477.1471; m/z: [M + K]+ calcd for C25H26KO8, 493.1259;
found, 493.1220.
4.2.9. 2-(4-Hydroxy-3-methoxyphenyl)-6-methyl-4H-pyran-4-
one, 2. TfOH (2.4 μL, 27.12 mmol, 1.0 equiv) was added dropwise
to a solution of 1-(3-methoxy-4-(methoxymethoxy)phenyl)hexa-1,4-
diyn-3-one 20 in deionized water (77 mL), and the mixture was
stirred 4 h at 100 °C with a heating mantle (CCM, SiO2, EtOAc/
MeOH, 9:1). After cooling to room temperature, the reaction mixture
was diluted with water (20 mL) and EtOAc (20 mL). The organic
phase was separated, and the aqueous phase was further extracted
with EtOAc (3 × 20 mL). The combined organic phases were washed
with water (3 × 20 mL) and brine (3 × 20 mL) and then dried over
Na2SO4 and filtered. The filtrate was chromatographed (SiO2 and
EtOAc/MeOH, 9:1) and afforded compound 2 as a white solid (4.95
g, 79%). Rf: 0.34 (EtOAc/MeOH, 9:1). mp 112 °C. IR (ATR, cm−1):
4.2.12. (E)-2-(4-Hydroxy-3-methoxyphenyl)-6-(4-hydroxy-3-me-
thoxystyryl)-4H-pyran-4-one, 1. To a stirred solution of (E)-2-(3-
methoxy-4-(methoxymethoxy)phenyl)-6-(3-methoxy-4-
(methoxymethoxy)styryl)-4H-pyran-4-one 22 (170 mg, 0.37 mmol)
in MeOH (10 mL), an excess of HCl 1 M was added dropwise at
room temperature (3 mL, 3.00 mmol, 8.02 equiv). The mixture was
then refluxed with a heating mantle for 3 h, and the reaction
advancement was followed by CCM (SiO2 and EtOAc/MeOH, 95:5).
At the end, the reaction was quenched with water (10 mL), and the
precipitated product was filtered, washed with water, and finally dried
to afford 2,6-γ-pyrone 1 as a yellow solid (125 mg, 91%). Rf: 0.33
(EtOAc/MeOH, 95:5). mp: 238 °C. IR (ATR, cm−1): 3134 (br),
1
3410, 1651, 1645, 1520, 856. UV−Vis (DMSO): 316 nm. H NMR
(400 MHz, CDCl3): δ 7.33 (dd, JH,H = 8.4, 2.1 Hz, 1H; Ar-H), 7.19
(d, JH,H = 2.1 Hz, 1H; Ar-H), 7.00 (d, JH,H = 8.4 Hz, 1H; Ar-H), 6.62
(d, JH,H = 2.2 Hz, 1H; Hpyrone), 6.17 (dd, JH,H = 2.0, 0.6 Hz, 1H;
1
H
pyrone), 3.95 (s, 3H; OCH3), 2.37 (d, JH,H = 0.5 Hz, 3H; CH3).
2932, 1641, 1628, 1595, 1508. H NMR (400 MHz, DMSO-d6): δ
13C{1H} NMR (100 MHz, CDCl3): δ 180.6, 165.4, 164.0, 149.1,
9.87 (s, 1H; OH), 9.56 (s, 1H; OH), 7.58 (dd, JH,H = 8.3, 2.2 Hz, 1H;
Ar-H), 7.52 (d, JH,H = 16.1 Hz, 1H; Hβ), 7.52 (d, JH,H = 2.1 Hz, 1H;
Ar-H), 7.37 (d, JH,H = 1.9 Hz, 1H; Ar-H), 7.19 (dd, JH,H = 8.3, 1.9 Hz,
1H; Ar-H), 7.01 (d, JH,H = 16.1 Hz, 1H; Hα), 6.99 (d, JH,H = 8.3 Hz,
1H; Ar-H), 6.86 (d, JH,H = 7.8 Hz, 1H; Ar-H), 6.85 (d, JH,H = 2.1 Hz,
1H; Hpyrone), 6.32 (d, JH,H = 2.2 Hz, 1H; Hpyrone), 3.94 (s, 3H; OCH3),
3.89 (s, 3H; OCH3). 13C{1H} NMR (100 MHz, DMSO-d6): δ 180.0,
163.2, 162.6, 151.0, 149.6, 149.0, 148.95, 136.7, 127.7, 123.3, 122.9,
120.7, 117.9, 116.8, 116.6, 113.2, 111.8, 110.7, 109.8, 56.8, 56.7. ESI-
MS (HR) m/z: [M + H]+ calcd for C21H19O6, 367.1176; found,
367.1184; m/z: [M + Na]+ calcd for C21H18NaO6, 389.0996; found,
389.0967.
147.2, 123.4, 120.2, 115.2, 114.2, 109.5, 108.2, 56.2, 20.0. ESI-MS
(HR) m/z: [M + H]+ calcd for C13H13O4, 233.0808; found, 233.0812.
4.2.10. 2-(3-Methoxy-4-(methoxymethoxy)phenyl)-6-methyl-4H-
pyran-4-one, 21. To a solution of 2-(4-hydroxy-3-methoxyphenyl)-6-
methyl-4H-pyran-4-one 2 (40 mg, 0.17 mmol) in DCM (5 mL) were
added DIPEA (67 μL, 0.26 mmol, 1.50 equiv) and MOM chloride
(20 μL, 0.38 mmol, 2.21 equiv) under stirring at 0 °C. After addition,
the flask was sealed, and the mixture was stirred for 3 h at room
temperature (CCM, SiO2, and EtOAc). The reaction mixture was
quenched with saturated aqueous NH4Cl (3 mL), and the organic
phase was separated. The aqueous phase was further extracted with
DCM (3 × 5 mL). The combined organic phases were washed with
water (3 × 5 mL) and brine (3 × 5 mL) and then dried over Na2SO4,
filtered, concentrated, and purified by chromatography (SiO2 and
EtOAc) to afford protected derivative 21 as a white solid (47 mg,
98%). Rf: 0.30 (EtOAc). mp 158 °C. IR (ATR, cm−1): 1655, 1612,
1512, 858. UV−Vis (DMSO): 310 nm. 1H NMR (400 MHz, CDCl3):
δ 7.29 (dd, JH,H = 8.5, 2.2 Hz, 1H; Ar-H), 7.19 (d, JH,H = 2.1 Hz, 1H;
Ar-H), 7.17 (d, JH,H = 8.5 Hz, 1H; Ar-H), 6.57 (d, JH,H = 2.2 Hz, 1H;
4.2.13. (Z)-2-(4-Hydroxy-3-methoxyphenyl)-6-(4-hydroxy-3-me-
thoxystyryl)-4H-pyran-4-one, 1. An irradiation at 375 nm of the
1
solution of 1 in DMSO led to 1′ with a ratio: 1/1′ 47:53. H NMR
(400 MHz, DMSO-d6): δ 9.58 (s, 1H; OH), 9.36 (s, 1H; OH), 7.00
(d, JH,H = 1.5 Hz, 1H; Ar-H), 6.97 (d, JH,H = 1.9 Hz, 1H; Ar-H), 6.94
(d, JH,H = 12.0 Hz, 1H; Hβ), 6.88 (m, 1H; Ar-H), 6.83 (d, JH,H = 2.2
Hz, 1H; Hpyrone), 6.80 (dd, JH,H = 8.4, 2.1 Hz, 1H; Ar-H), 6.77 (d, JH,H
= 8.1 Hz, 1H; Ar-H), 6.70 (d, JH,H = 8.4 Hz, 1H; Ar-H), 6.33 (d, JH,H
= 2.6 Hz, 1H; Hpyrone), 6.32 (d, JH,H = 12.0 Hz, 1H; Hα), 3.62 (s, 3H;
OCH3), 3.56 (s, 3H; OCH3). 13C{1H} NMR (100 MHz, DMSO-d6):
δ 179.7, 163.3, 162.5, 150.8, 148.6, 148.4, 148.2, 138.7, 127.9, 123.5,
122.3, 120.5, 119.5, 116.3, 116.2, 115.7, 113.7, 110.1, 109.7, 56.3,
56.2. ESI-MS (HR) m/z: [M + H]+ calcd for C21H19O6, 367.1184;
found, 367.1199; m/z: [M + Na]+ calcd for C21H18NaO6, 389.0996;
found, 389.0967.
H
pyrone), 6.10 (dd, JH,H = 2.1, 0.7 Hz, 1H; Hpyrone), 5.23 (s, 2H;
OCH2O), 3.89 (s, 3H; OCH3), 3.47 (s, 3H; OCH3), 2.32 (d, JH,H
=
0.6 Hz, 3H; CH3). 13C{1H} NMR (100 MHz, CDCl3): δ 180.2,
165.2, 163.4, 149.9, 149.2, 125.3, 119.2, 115.9, 114.2, 109.9, 109.0,
95.2, 56.4, 56.1, 19.9. ESI-MS (HR) m/z: [M + H]+ calcd for
C15H17O5, 277.1071; found, 277.1088; m/z: [M + Na]+ calcd for
C15H16NaO5, 299.0890; found, 299.0899.
4.3. Computational Methodology. The GS minima of both
isomers of the prepared γ-pyrone analogue of CC 1 was found under
the framework of DFT, applying the B3LYP functional.45
To compute the absorption spectra of both isomers, time-
dependent DFT (TD-DFT) was used. Different DFT functionals
and basis sets were used to characterize the excitation of the molecule
using Gaussian16 software.46 As more remarkable, two main
4.2.11. (E)-2-(3-Methoxy-4-(methoxymethoxy)phenyl)-6-(3-me-
thoxy-4-(methoxymethoxy)styryl)-4H-pyran-4-one, 22. A freshly
prepared NaOEt solution (1.478 M in EtOH, 2.2 mL, 3.25 mmol,
1.79 equiv) was added dropwise to a mixture of 2-(3-methoxy-4-
(methoxymethoxy)phenyl)-6-methyl-4H-pyran-4-one 21 (500 mg,
1.81 mmol) and 3-methoxy-4-(methoxymethoxy)benzaldehyde 3c
(510 mg, 2.59 mmol, 1.43 equiv) in dry EtOH (20 mL) at room
8123
J. Org. Chem. 2021, 86, 8112−8126