The Journal of Organic Chemistry
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7.4 Hz, 2H), 2.09−1.95 (m, 1H), 1.94−1.80 (m, 1H), 1.25 (t, J = 7.1
Hz, 3H), 1.21 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 178.4, 173.3,
150.4, 128.4, 127.7, 124.7, 118.6, 109.4, 66.2, 61.8, 60.5, 47.4, 38.8,
31.4, 30.9, 27.2 (3C), 14.2; MS (EI, 70 eV) m/z (%) 333 (M+, 6), 231
(25), 186 (22), 185 (39), 184 (72), 144 (21), 130 (100), 117 (12), 77
(8), 55 (21). Minor diastereomer (cis): MS (EI, 70 eV) m/z (%) 333
(M+, 5), 231 (27), 186 (20), 185 (51), 184 (100), 144 (32), 130 (89),
117 (19), 77 (10), 57 (40).
mmol) and m-CPBA (77% purity, 3.88 g, 17.33 mmol) in dry CH2Cl2
(23 mL) for the oxidation step followed by 10% KOH (7.80 mL, 13.86
mmol) in MeOH (5 mL) for the saponification step. Purification by
flash column chromatography (cyclohexane/AcOEt 10:1) gave 11
(1.62 g, 9.63 mmol, 83%) as a yellowish solid. Physical and spectral
data were in accordance with literature data:22 mp 32−34 °C; H
1
NMR (300 MHz, CDCl3) δ 6.75 (d, J = 8.8 Hz, 1H), 6.54 (d, J = 8.8
Hz, 1H), 5.25 (s, 1H), 3.78 (s, 3H), 3.77 (s, 3H), 2.17 (s, 3H); 13C
NMR (75 MHz, CDCl3) δ 151.9, 146.0, 142.9, 120.0, 111.6, 106.8,
60.8, 56.1, 9.3; MS (EI, 70 eV) m/z (%) 169 (9), 168 (M+, 100), 153
(78), 138 (8), 125 (52), 110 (21), 93 (9), 79 (11), 65 (20), 53 (11).
(E)-1-((4-Bromobut-2-en-1-yl)oxy)-2,4-dimethoxy-3-methyl-
benzene (12). To a solution of 11 (2.09 g, 12.43 mmol) in acetone
(63 mL) at rt under argon was added trans-1,4-dibromo-2-butene
(13.29 g, 62.14 mmol) followed by K2CO3 (3.43 g, 24.86 mmol). The
reaction mixture was refluxed for 18 h. The mixture was cooled to rt,
K2CO3 was removed by filtration (rinsed with acetone), and the
filtrate was concentrated under reduced pressure. Purification by flash
column chromatography (cyclohexane/AcOEt 30:1) gave 12 (3.03 g,
10.06 mmol, 81%) as a yellowish liquid: 1H NMR (300 MHz, CDCl3)
δ 6.69 (d, J = 8.9 Hz, 1H), 6.51 (d, J = 8.9 Hz, 1H), 6.13−5.95 (m,
2H), 4.54 (d, J = 4.1 Hz, 2H), 3.99 (d, J = 6.4 Hz, 2H), 3.81 (s, 3H),
3.78 (s, 3H), 2.15 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 153.0,
148.9, 145.8, 130.8, 128.8, 121.3, 112.0, 105.2, 69.0, 60.4, 55.9, 31.8,
8.9; IR (neat) 2999, 2934, 2832, 1593, 1483, 1462, 1377, 1254, 1221,
1205, 1108, 1061, 1023, 964, 787; MS (EI, 70 eV) m/z (%) 302 (5),
300 (M+, 5), 220 (4), 168 (17), 167 (100), 139 (31), 124 (23), 107
(17), 91 (6), 79 (7), 65 (5), 53 (19); HRMS (ESI) calcd for
C13H18BrO3 301.0439, found 301.0441.
(E)-1-((4-(Benzyloxy)but-2-en-1-yl)oxy)-2,4-dimethoxy-3-
methylbenzene (13). To a solution of benzyl alcohol (0.45 mL, 4.32
mmol) in dry THF (21 mL) at 0 °C under argon was added NaH
(55% dispersion in oil, 290 mg, 6.64 mmol) portionwise. The mixture
was stirred at rt for 30 min, then a solution of 12 (1.00 g, 3.32 mmol)
in dry THF (5 mL) was added at 0 °C followed by tetrabutyl-
ammonium iodide (92 mg, 0.25 mmol) after 10 min. The mixture was
stirred at rt for 18 h. Et2O (10 mL) was added followed by water
dropwise (5 mL) and brine (5 mL). The two layers were separated,
and the aqueous layer was extracted with Et2O (3 × 5 mL). The
combined organic layers were washed with brine (1 × 5 mL), dried
over Na2SO4, filtered, and concentrated under reduced pressure.
Purification by flash column chromatography (cyclohexane/AcOEt
15:1) gave 13 (937 mg, 2.85 mmol, 86%) as a yellowish oil: 1H NMR
(300 MHz, CDCl3) δ 7.37−7.26 (m, 5H), 6.71 (d, J = 8.9 Hz, 1H),
6.50 (d, J = 8.9 Hz, 1H), 6.05−5.90 (m, 2H), 4.56−4.52 (m, 2H), 4.52
(s, 2H), 4.10−4.04 (m, 2H), 3.81 (s, 3H), 3.77 (s, 3H), 2.15 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 152.9, 148.9, 146.0, 138.2, 129.6,
(3-Oxo-2,3,9,9a-tetrahydro-1H-pyrrolo[1,2-a]indol-9-yl)-
methyl acetate (9b). To a solution of 8b [48 mg, 0.17 mmol, trans/
1
cis (93:7) as determined by H NMR] in dry toluene (1.5 mL) was
added (+)-camphor-10-sulfonic acid (CSA) (8 mg, 0.03 mmol). The
mixture was stirred at reflux for 2 h, cooled to rt, and the solvent was
removed under reduced pressure. Purification by flash column
chromatography (cyclohexane/AcOEt 3:2) gave 9b (34 mg, 0.14
mmol, 82%, trans/cis 99:1 as determined by GC) as a white solid. The
diastereomers were not completely separable. Mixture of diaster-
eomers: mp 115−119 °C; IR (neat) 2973, 2907, 1736, 1695, 1602,
1482, 1463, 1401, 1364, 1236, 1126, 1034, 755; HRMS (ESI) calcd for
C14H15NO3Na 268.0944, found 268.0943; GC tR (major) 23.72 min;
tR (minor) 23.47 min (60 °C, 0 min, 60−280 °C, 8 °C/min, 280 °C,
15 min). Major diastereomer (trans): 1H NMR (300 MHz, CDCl3) δ
7.63 (d, J = 7.8 Hz, 1H), 7.31−7.24 (m, 1H), 7.20 (d, J = 7.6 Hz, 1H),
7.08 (t, J = 7.6 Hz, 1H), 4.60 (dd, J = 11.1, 5.3 Hz, 1H), 4.46−4.35 (m,
1H), 4.30 (dd, J = 11.1, 8.5 Hz, 1H), 3.58−3.48 (m, 1H), 2.93−2.79
(m, 1H), 2.61 (dd, J = 16.6, 8.4 Hz, 1H), 2.54−2.42 (m, 1H), 2.11 (s,
3H), 2.10−2.00 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 171.3, 170.7,
139.4, 133.5, 128.6, 124.4, 124.3, 115.0, 67.4, 65.2, 48.0, 36.0, 28.7,
20.8; MS (EI, 70 eV) m/z (%) 245 (M+, 8), 185 (48), 184 (100), 172
(15), 156 (9), 130 (40), 117 (11), 103 (8), 77 (9), 55 (75), 43 (23).
Minor diastereomer (cis): MS (EI, 70 eV) m/z (%) 245 (M+, 10), 185
(50), 184 (100), 172 (11), 156 (9), 130 (51), 117 (11), 103 (5), 77
(9), 55 (56), 43 (21).
(3-Oxo-2,3,9,9a-tetrahydro-1H-pyrrolo[1,2-a]indol-9-yl)-
methyl pivalate (9c). The compound was prepared using the same
procedure as for 9b, from 8c (1.30 g, 3.90 mmol, trans/cis 97:3 as
determined by GC) and CSA (181 mg, 0.78 mmol) in dry toluene (35
mL). Purification by flash column chromatography (cyclohexane/
AcOEt 4:1) gave 9c (969 mg, 3.37 mmol, 86%, trans/cis > 99:1 as
determined by GC) as a white solid. The diastereomers were not
completely separable. Mixture of diastereomers: mp 84−86 °C; IR
(neat) 2971, 2875, 1725, 1698, 1601, 1479, 1460, 1397, 1351, 1282,
1155, 757; HRMS (ESI) calcd for C17H22NO3 288.1594, found
288.1589; GC tR (major) 23.95 min, tR (minor) 23.71 min (60 °C, 0
min, 60−280 °C, 8 °C/min, 280 °C, 15 min). Major diastereomer
1
(trans): H NMR (300 MHz, CDCl3) δ 7.63 (d, J = 7.8 Hz, 1H),
7.31−7.24 (m, 1H), 7.20 (d, J = 7.5 Hz, 1H), 7.07 (td, J = 7.5, 0.9 Hz,
1H), 4.57 (dd, J = 11.1, 5.0 Hz, 1H), 4.45−4.37 (m, 1H), 4.30 (dd, J =
11.1, 8.6 Hz, 1H), 3.58−3.48 (m, 1H), 2.94−2.80 (m, 1H), 2.61 (dd, J
= 16.5, 8.3 Hz, 1H), 2.55−2.45 (m, 1H), 2.14−1.98 (m, 1H), 1.21 (s,
9H); 13C NMR (100 MHz, CDCl3) δ 178.3, 171.4, 139.4, 133.5,
128.6, 124.4, 124.3, 115.1, 67.7, 65.2, 48.2, 38.9, 36.0, 28.7, 27.2 (3C);
MS (EI, 70 eV) m/z (%) 287 (M+, 2), 186 (10), 185 (44), 184 (100),
172 (6), 156 (5), 130 (14), 117 (3), 103 (3), 77 (4), 57 (16), 55 (30).
Minor diastereomer (cis): MS (EI, 70 eV) m/z (%) 287 (M+, 2), 186
(11), 185 (42), 184 (100), 172 (11), 156 (8), 130 (21), 117 (8), 103
(7), 77 (8), 57 (22), 55 (39).
2,4-Dimethoxy-3-methylbenzaldehyde (10). The compound
was prepared according to Zhu’s procedure22 from 2,6-dimethoxy-
toluene (3.88 g, 25.00 mmol) and POCl3 (2.80 mL, 30.60 mmol) in
dry DMF (10 mL). Purification by flash column chromatography
(cyclohexane/AcOEt 10:1) gave 10 (3.20 g, 17.77 mmol, 71%) as a
yellowish solid. Physical and spectral data were in accordance with
literature data:22 mp 52−55 °C; 1H NMR (300 MHz, CDCl3) δ 10.23
(s, 1H), 7.74 (d, J = 8.7 Hz, 1H), 6.75 (d, J = 8.7 Hz, 1H), 3.91 (s,
3H), 3.86 (s, 3H), 2.16 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 189.1,
164.0, 162.6, 128.0, 122.8, 120.1, 106.5, 63.2, 55.9, 8.5; HRMS (ESI)
calcd for C10H13O3 181.0859, found 181.0864.
128.6, 128.4 (2C), 127.8 (2C), 127.6, 121.2, 111.9, 105.2, 72.2, 70.0,
69.5, 60.4, 55.9, 8.9; IR (neat) 2935, 2855, 1592, 1484, 1454, 1359,
1254, 1222, 1107, 1058, 1025, 967, 788, 734, 696; MS (EI, 70 eV) m/z
(%) 328 (M+, 27), 237 (39), 220 (44), 207 (35), 176 (19), 175 (100),
147 (40), 105 (13), 91 (77), 77 (13), 65 (11); HRMS (ESI) calcd for
C20H24O4Na 351.1567, found 351.1574.
6-(1-(Benzyloxy)but-3-en-2-yl)-2,4-dimethoxy-3-methylphe-
nol (14). A solution of 13 (900 mg, 2.74 mmol) in N,N-diethylaniline
(15 mL) at rt was thoroughly degassed with argon for 5 min under a
slight vacuum. The mixture was then stirred at 215 °C for 4 h. The
mixture was cooled to rt, diluted with AcOEt (10 mL), and acidified
with 1 N HCl to pH 1−2. The aqueous layer was extracted with
AcOEt (3 × 10 mL). The combined organic layers were dried over
Na2SO4, filtered, and concentrated under reduced pressure.
Purification by flash column chromatography (cyclohexane/AcOEt
1
20:1) gave 14 (819 mg, 2.49 mmol, 91%) as a yellow oil: H NMR
(300 MHz, CDCl3) δ 7.36−7.26 (m, 5H), 6.42 (s, 1H), 6.11 (ddd, J =
17.2, 10.5, 6.8 Hz, 1H), 6.00 (br s, 1H), 5.20−5.16 (m, 1H), 5.13 (dt, J
= 10.5, 1.5 Hz, 1H), 4.56 (s, 2H), 4.03−3.94 (m, 1H), 3.82−3.70 (m,
8H), 2.14 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 151.3, 146.5,
141.2, 138.1, 137.8, 128.3 (2C), 127.7 (2C), 127.6, 124.8, 118.3, 116.0,
106.6, 73.2, 73.1, 60.7, 56.1, 44.2, 9.2; IR (neat) 3322 (br), 2938, 2858,
2832, 1595, 1488, 1455, 1412, 1357, 1186, 1119, 1021, 997, 915, 735,
2,4-Dimethoxy-3-methylphenol (11). The compound was
prepared according to Zhu’s procedure22 from 10 (2.08 g, 11.55
F
dx.doi.org/10.1021/jo4009904 | J. Org. Chem. XXXX, XXX, XXX−XXX