F. Mazzini, F. Galli, P. Salvadori
FULL PAPER
After 3 h at 0 °C, the white suspension was allowed to rise to room
temp. and stirred overnight. The mixture was then made acidic with
HClconc and THF evaporated. After work up in EtOAc, the residue
was purified by column chromatography (CH2Cl2) to afford 13
stirred solution of 16 (400 mg, 2.3 mmol) in CH3CN (6 mL). After
20 min, TLC (Hex/EtOAc, 10:1) showed complete conversion of
the reagent. Water was added to the red solution, and after the
usual work up in CH2Cl2, the residue was purified by passage
through a short plug of silica gel (CH2Cl2) to afford pure 17
(280 mg, 88% yield) as a yellow solid. M.p. 57–59 °C 1H NMR
1
(1.01 g, 71% yield) as a white crystalline solid. M.p. 72–75 °C. H
NMR (300 MHz, CDCl3): δ = 2.28 (s, 3 H), 4.87 (br. s, 1 H), 6.63
(d, J = 8.1 Hz, 1 H), 6.77 (d, J = 7.2 Hz, 1 H), 6.98 (t, J = 7.7 Hz, (300 MHz, CDCl3): δ = 2.00 (s, 3 H), 6.67 (s, 2 H) ppm. 13C NMR
1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 11.5 (m), 20.0, 112.6,
122.3, 122.4, 126.0, 138.3, 153.5 ppm. GC–MS (EI): m/z (%) = 125
(100), 110 (54). C8H7D3O (125.2): calcd. C 76.76, H 10.46; found
C 76.85, H 10.44. Isotope purity of 99.0% by GC–MS (99.0% [D3]-
, 0.8% [D2]- and 0.2% [D1]-13).
(75 MHz, CDCl3): δ = 12.3 (m), 136.4, 141.2, 187.5 ppm. GC–MS
(EI): m/z (%) = 139 (56), 111 (100). C8H5D3O2 (139.2): calcd. C
69.04, H 7.96; found C 69.21, H 7.98. Isotope purity of 98.9% by
GC–MS (98.9% [D3]-, 0.9% [D2]- and 0.2% [D1]-17).
1,4-Dihydroxy-2-[(2H3)methyl]-3-methylbenzene
(18):
NaBH4
1-Methoxy-2-[(2H3)methyl]-3-methylbenzene (14): To a stirred sus-
pension of dry NaH (150 mg, 6 mmol, 1.2 equiv.) in dry DMF
(4 mL) was added a solution of phenol 13 (630 mg, 5 mmol) in dry
DMF (6 mL). The reaction mixture was stirred for 40 min and then
cooled to 0 °C. A solution of CH3I (0.38 mL, 6 mmol, 1.2 equiv.)
in dry DMF (4 mL) was then added dropwise. The reaction mixture
was warmed to room temp. and stirred for 2 h. The end of the
reaction was confirmed by TLC (Hex/EtOAc, 5:1). Water (10 mL)
was added, and after usual work up in Et2O, pure 14 (620 mg, 89%
yield) was obtained as a nearly colourless oil. 1H NMR (300 MHz,
CDCl3): δ = 2.37 (s, 3 H), 3.90 (s, 3 H), 6.81 (d, J = 8.4 Hz, 1 H),
6.87 (d, J = 8.7 Hz, 1 H), 7.16 (t, J = 7.8 Hz, 1 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 11.7 (m), 20.3, 55.7, 108.1, 122.5, 125.1,
126.1, 138.1, 157.9 ppm. GC–MS (EI): m/z (%) = 139 (100), 124
(79). C9H9D3O (139.2): calcd. C 77.65, H 10.86; found C 77.55, H
10.89. Isotope purity of 99.0% by GC–MS (99.0% [D3]-, 0.8%
[D2]- and 0.2% [D1]14).
(80 mg, mmol, 1.2 equiv.) was added to a solution of 15 (250 mg,
1.7 mmol) in MeOH/H2O (5:1, 6 mL) at 0 °C. After 20 min, TLC
(Hex/EtOAc, 3:1) showed complete conversion of the reagent.
Water was added, and the mixture was made acidic with HCl (1 ).
After the usual work up in EtOAc, the residue was purified by
passage through a short plug of silica gel (Hex/EtOAc, 3:1) to af-
1
ford 18 (220 mg, 91% yield) as a white solid. M.p. 226–228 °C. H
NMR (300 MHz, CD3OD): δ = 2.09 (s, 3 H), 4.86 (br. s, 2 H), 6.45
(s, 2 H) pm. 13C NMR (75 MHz, CD3OD): δ = 13.0 (m), 13.1,
114.1, 126.1, 1499 ppm. GC–MS (EI): m/z (%) = 141 (100), 125
(32). C8H7D3O2 (141.2): calcd. C 68.06, H 9.28; found C 68.21, H
9.26. Isotope purity of 98.9% by GC–MS (98.9% [D3]-, 0.9% [D2]-
and 0.2% [D1]-18).
Racemic
2-(2Ј-Carboxyethyl)-6-hydroxy-7-[(2H3)Methyl]-2,8-di-
methylchroman (19a) and 2-(2Ј-Carboxyethyl)-6-hydroxy-8-[(2H3)-
Methyl]-2,7-dimethylchroman (19b) Mixture: A solution of lactone
1 (250 mg, 2 mmol, 1.5 equiv.) in anhydrous 1,4-dioxane (3 mL)
was added over 1 h to a stirred solution of 18 (190 mg, 1.35 mmol),
anhydrous ZnCl2 (370 mg, 2.7 mmol, 2 equiv.), HClconc (0.02 mL)
in anhydrous 1,4-dioxane (3 mL). The mixture was heated at reflux
for 2 h. Dioxane was evaporated, water was added, and after the
usual work up in EtOAc, the residue was purified by flash
chromatography (Hex/EtOAc/AcOH, 2:1:0.003). The brown semi-
solid was recrystallized from Hex/Et2O, 1:1 at 0 °C to afford
19a+19b (150 mg, 43% yield) as a white solid. According to the
NMR peaks assignment reported by Wechter,[7] the mixture com-
position was calculated from 2H NMR: 2.05 (8a CD3, 19b): 2.08
(7a CD3, 19a) peaks ratio, 19a/19b = 53:47. M.p. 144–148 °C 1H
NMR (300 MHz, CD3OD): δ = 1.20 (s, 3 H), 1.71–1.95 (m, 4 H),
2.04 and 2.06 (two singlets, their sum 3 H, ArCH3 19a and 19b,
respectively), 2.43 (m, 2 H), 2.65 (m, 2 H), 4.91 (br. s, 2 H), 6.33
4-Bromo-1-methoxy-2-[(2H3)methyl]-3-methylbenzene (15): A solu-
tion of BTMABr3 (1.45 g, 3.7 mmol) in CH2Cl2 (16 mL) was added
dropwise to a stirred solution of 14 (510 mg, 3.7 mmol) in MeOH/
CH2Cl2 (2:3, 25 mL). After 1.5 h, TLC (Hex) showed complete
conversion of the reagent. NaHSO3 (5%, 4 mL) was added, and
the mixture was stirred for 15 min. Water was added, MeOH evapo-
rated, and after the usual work up in Et2O, the residue was purified
by passage through a short plug of silica gel (Et2O) to afford pure
1
15 (740 mg, 92% yield) as a pale yellow oil. H NMR (300 MHz,
CDCl3): δ = 2.43 (s, 3 H), 3.85 (s, 3 H), 6.64 (d, J = 8.7 Hz, 1 H),
7.40 (d, J = 8.7 Hz, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
11.9 (m), 19.8, 55.7, 109.4, 116.3, 126.8, 129.6, 136.8, 156.7 ppm.
GC–MS (EI): m/z (%) = 217 (100), 219 (98), 202 (46), 204 (44).
C9H8D3BrO (218.1): calcd. C 49.56, H 6.47, Br 36.64; found C
49.72, H 6.45, Br 36.57. Isotope purity of 99.0% by GC–MS
(99.0% [D3]-, 0.8% [D2]- and 0.2% [D1]-15).
2
(s, 1 H) ppm. H NMR (46 MHz, CH3OH): δ = 2.05 (s), 2.08 (s)
ppm. 13C NMR (75 MHz, CD3OD): δ = 12.7–12.8 (m), 24.0, 24.7,
30.4, 33.4, 36.7, 76.2, 113.9, 119.7, 124.1, 127.1, 146.6, 149.7,
178.6 ppm. APCI-LC–MS (MeOH, negative ion mode) m/z = 266
[M – H]–. C15H17D3O4 (267.3): calcd. C 67.39, H 8.67; found C
67.15, H 8.63. Isotope purity of 98.9% by LC–MS (98.9% [D3]-,
0.9% [D2]- and 0.2% [D1]-19).
1,4-Dimethoxy-2-[(2H3)methyl]-3-methylbenzene (16): A solution of
NaOCH3 (4.37 ⁾ in MeOH (2.5 mL) was added to a DMF solu-
tion (2.5 mL) of 15 (700 mg, 3.2 mmol) and CuI (100 mg,
0.5 mmol). The resulting solution was heated at reflux for 7 h when
TLC (Hex) showed complete conversion of the reagent. An aque-
ous solution of NH3 (5%) was then added to remove the copper
catalyst, and after the usual work up in Et2O, the residue was puri-
fied by passage through a short plug of silica gel (Hex) to afford
pure 16 (470 mg, 88% yield) as a pale yellow solid. M.p. 76–78 °C
1H NMR (300 MHz, CDCl3): δ = 2.17 (s, 3 H), 3.78 (s, 6 H), 6.66
(s, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 12.2 (m), 56.2,
108.0, 126.8, 126.9, 152.1 ppm. GC–MS (EI): m/z (%) = 169 (100),
154 (90). C10H11D3O2 (169.2): calcd. C 70.97, H 10.12; found C
70.81, H 10.08. Isotope purity of 99.0% by GC–MS (99.0% [D3]-,
0.8% [D2]- and 0.2% [D1]-16).
Acknowledgments
We are grateful to Dr. A. Cuzzola and I. Bonaduce for MS analyses
and Dr. A. Mandoli and Dr. Th. Netscher for their useful dis-
cussions. The University of Perugia and MIUR, project “Strategie
innovative per la diagnosi e terapia del mesotelioma maligno della
pleura” are acknowledged for financial support.
[1] IUPAC-IUB, Eur. J. Biochem. 1982, 123, 473–475.
[2] R. Brigelius-Flohe, M. G. Traber, FASEB J. 1999, 13, 1145–
1155.
2-[(2H3)Methyl]-3-methyl-1,4-benzoquinone (17):
CAN (2.78 g, 5.1 mmol, 2.2 equiv.) in H2O (6 mL) was added to a
A solution of
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Eur. J. Org. Chem. 2006, 5588–5593