Synthesis of the aromatic unit of calicheamicin γ1 I

Article abstract of DOI:10.1039/a605837j

Vanillin and piperonal are each converted into methyl 2,3-dimethoxy-6-methyl-4-(prop-2-enyl)benzoate 12, and this is then elaborated into methyl 4-hydroxy-3-iodo-5,6-dimethoxy-2-methylbenzoate 24, which represents the aromatic unit of calicheamicin γ₁^I.

Full text of DOI:10.1039/a605837j

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I
Synthesis of the aromatic unit of calicheamicin ã1
Yong-Zhou Hu and Derrick L. J. Clive*
Chemistry Department, University of Alberta, Edmonton, Alberta, T6G 2G2 Canada
Vanillin and piperonal are each converted into methyl 2,3-dimethoxy-6-methyl-4-(prop-2-enyl)benzoate 12,
and this is then elaborated into methyl 4-hydroxy-3-iodo-5,6-dimethoxy-2-methylbenzoate 24, which
I
represents the aromatic unit of calicheamicin ã1 .
The aromatic system 1 (R, RЈ = complex carbohydrate) is a
conditions (allyl bromide, K2CO3, 96%) and Claisen
I
structural unit of the antitumour agent calicheamicin γ1 .1
rearrangement (ca. 190 ЊC, 91%) served to functionalize the
expected position of the aromatic ring (9→10) and methyl-
ation (Me2SO4, K2CO3, 92%) then gave the fully protected
bromide 11. At this point, halogen-metal exchange (BunLi)
and quenching with methyl chloroformate yielded ester 12
(81%). This substance is common to both of our routes, as
it was also prepared from piperonal, as described below
(Scheme 2).
Methods for making the parent system 2 (R = H)2 and the
corresponding ester (2, R = Me)2,3 and nitrile 34 have been
reported. We describe here two further routes to 2 (R = Me).
CHO
CHNC6H11
CHO
BunLi
CO2Me
C6H11NH2
MeOCOCl
H3O+
88%
ca. 97%
Our first route begins with the known nitro acetate 6,5 which
was made from vanillin, according to the literature procedure5
(Scheme 1, 4→5†,6→6). Reduction of both the nitro and formyl
O
O
O
O
O
O
13
14
15
Pd–C, H2
93%
Me
Me
Me
Li2CO3
MeI
CO2Me
CO2Me
CO2Me
DMF
AlBr3
93%
71%a
OMe
OH
O
O
OH
OH
18
17
16
K2CO3
allyl bromide
92%
Me
Me
Me
CO2Me
CO2Me
CO2Me
K2CO3
ca.190 °C
Me2SO4
97%
86%
OMe
OMe
OMe
O
OH
OMe
19
20
12
aAfter correction for recovered 17 (30%)
Scheme 2
Aldehyde ester 15 was made from piperonal by a literature
procedure7 (Scheme 2, 13→14→15), and then the formyl
group was completely reduced 8 (15→16, Pd–C, H2, 93%).
Deprotection of the phenolic hydroxy groups (16→17, 93%)
was accomplished by the action of aluminum bromide,9 and the
resulting pyrocatechol 17 was then methylated regioselectively
under conditions10 (DMF, MeI, Li2CO3) that afforded the
monomethyl ether 18 in 50% yield [71%, after allowing for
recovered starting material (30%)]. The remaining hydroxy
group was then allylated as before (18→19, allyl bromide
K2CO3, 92%) and then Claisen rearrangement (19→20, ca.
190 ЊC, 86%) and subseqent methylation (Me2SO4, K2CO3,
97%) resulted in formation again of the highly substituted ester
Scheme 1
groups (6→7, Pd–C, H2, 93%), followed by Sandmeyer reaction
(NaNO2, HCl, CuBr) and hydrolysis (KOH) afforded
bromophenol 8 (81% from 7). Allylation (8→9) under classical
† The literature procedure was followed for the preparation of 5, except
that the Ac2O (4.09 cm3, 43.3 mmol) was dissolved in Et2O (36 cm3),
instead of being used neat. The crude product (94%) was used directly.
J. Chem. Soc., Perkin Trans. 1, 1997
1421

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3-Bromo-2-methoxy-4-methylphenol 8
NaNO2 (1.45 g, 21.03 mmol) in water (4 cm3) was added drop-
wise over 30 min to a stirred and cooled (Ϫ5 to 0 ЊC) solution of
7 (4.02 g, 20.61 mmol) in hydrobromic acid (48%; 7.5 cm3).
After the addition, stirring was continued for 25 min, and the
solution of the diazonium salt was then added dropwise to a
stirred and heated (100 ЊC) solution of CuBr (1.96 g, 13.60
mmol) in hydrobromic acid (48%; 4.5 cm3). At the end of the
addition, stirring was continued for 15 min, and the mixture was
then cooled to room temperature and extracted with Et2O
(3 × 25 cm3). The combined extracts were washed with hydro-
chloric acid (3%; 2 × 125 cm3), water (20 cm3) and saturated
aqueous NaHCO3 (15 cm3). The organic phase (without drying)
was evaporated and the residue was diluted with MeOH (50
cm3). KOH (3.0 g, 75.0 mmol) was added, the the mixture was
stirred at 70 ЊC (oil bath) for 1.5 h. The mixture was cooled to
room temperature, and concentrated. The residue was poured
into a mixture of ice (ca. 50 g) and concentrated aqueous HCl
(30 cm3), and the mixture was extracted with Et2O (3 × 20 cm3),
washed with saturated aqueous NaHCO3 (20 cm3), water (15
cm3) and brine (20 cm3) and dried (Na2SO4). Evaporation of the
solvent and flash chromatography of the residue over silica gel
(3 × 20 cm), using 1:6 EtOAc–hexane, gave 8 as a pure (1H
NMR, 300 MHz) oil (3.64 g, 81%); νmax(CH2Cl2 cast)/cmϪ1
3422, 2971, 2938, 1603, 1483, 1458, 1276, 1206 and 1037; δH (300
MHz, CDCl3) 2.34 (s, 3 H), 3.88 (s, 3 H), 5.66 (br s, 1 H), 6.82
(d, J 7.8, 1 H) and 6.91 (d, J 7.9, 1 H); δC(50.3 MHz, CDCl3)
22.25 (qЈ), 60.75 (qЈ), 114.39 (dЈ), 118.57 (dЈ), 126.22 (dЈ),
130.44 (sЈ), 144.36 (sЈ) and 147.51 (sЈ) (Found: Mϩ, 217.9769.
C8H981BrO2 requires M, 217.9765).
Scheme 3
12. This was converted into the target 2 (R = Me), as summar-
ized in Scheme 3.
The double bond in the pendant allyl group of 12 was isom-
erized 11 to the geometrical isomers 21 (RhCl3ؒH2O, EtOH,
70 ЊC, 89%, E :Z = 9:1), and oxidative cleavage (21→22, OsO4,
NaIO4, 83%) set the stage for the introduction of a hydroxy
group. This was accomplished 12 by Baeyer–Villiger oxidation
(22→23, MCPBA, 81%). Phenol 23 is a known substance2
which, on treatment with iodine chloride,2 gave the desired tar-
get 24 (i.e. 2, R = Me) in 95% yield.‡
2-Bromo-3-methoxy-1-methyl-4-(prop-2-enyloxy)benzene 9
Allyl bromide (1.68 cm3, 9.85 mmol) was added to a stirred
mixture of 8 (3.59 g, 16.5 mmol), anhydrous K2CO3 (4.12 g,
29.77 mmol) and dry acetone (65 cm3). The mixture was
refluxed with stirring for 7 h, cooled to room temperature and
filtered. The solid residue was washed with dry acetone and the
combined filtrates were evaporated. Flash chromatography of
the residue over silica gel (3.5 × 20 cm), using 1:20 EtOAc–
hexane, gave 9 (4.10 g, 96%) as a pure (1H NMR, 300 MHz),
colourless oil; νmax(CH2Cl2 cast)/cmϪ1 2979, 2933, 1595, 1484,
1458, 1395, 1293, 1268, 1257 and 1049; δH (300 MHz, CDCl3)
2.34 (s, 3 H), 3.87 (s, 3 H), 4.56 (dt, J 6.8, 1.5, 2 H), 5.28 (dq, J
10.4, 1.4, 1 H), 5.41 (dq, J 17.2, 1.5, 1 H), 5.98–6.11 (m, 1 H),
6.78 (d, J 8.3, 1 H) and 6.91 (d, J 8.4, 1 H); δC(50.3 MHz,
CDCl3) 22.34 (qЈ), 60.11 (qЈ), 69.70 (tЈ), 112.92 (dЈ), 117.33 (tЈ),
120.29 (sЈ), 124.92 (dЈ), 131.02 (sЈ), 132.97 (dЈ), 146.75 (sЈ) and
150.l22 (sЈ) (Found: Mϩ, 258.0077. C11H1381BrO2 requires M,
258.0078).
Experimental
General experimental procedures were the same as those used
previously.13 In the 13C NMR spectra the symbols sЈ, dЈ, tЈ and
qЈ represent 0, 1, 2 and 3 attached protons. J Values are given in
Hz.
4-Formyl-2-methoxy-3-nitrophenyl acetate 65
Aldehyde 5†,6 (7.4 g, 38.1 mmol) was added in portions to
stirred and cooled (Ϫ10 to Ϫ15 ЊC) fuming HNO3 (41 cm3) in a
100 cm3 flask at such a rate that the temperature did not rise
above Ϫ10 ЊC. Stirring was continued for 10 min after the add-
ition and the mixture was then poured onto cracked ice (ca. 200
g). The resulting solid was collected, washed with water and
recrystallized from a 1:1 mixture of 95% EtOH and water (100
cm3) to afford 6 (7.53 g, 83%) (lit.,5 27%), mp 82–83 ЊC (lit.,5
80 ЊC).
3-Amino-2-methoxy-4-methylphenyl acetate 7
3-Bromo-2-methoxy-4-methyl-6-(prop-2-enyl)phenol 10
A solution of 9 (2.20 g, 8.56 mmol) in decalin (3 cm3) was
refluxed for 6.5 h under Ar, cooled to room temperature and
evaporated. Flash chromatography of the residue over silica gel
(3 × 15 cm), using 1:20 EtOAc–hexane, gave 10 (2.01 g, 91%) as
a pure (1H NMR, 400 MHz), colourless oil; νmax(CH2Cl2 cast)/
cmϪ1 3507, 3003, 2976, 2938, 1639, 1459, 1401, 1299, 1210 and
1057; δH (400 MHz, CDCl3) 2.31 (s, 3 H), 3.34 (dd, J 3.5, 1.1, 2
H), 3.88 (s, 3 H), 5.05–5.10 (m, 2 H), 5.59 (s, 1 H), 5.92–6.03 (m,
1 H) and 6.80 (s, 1 H); δC(50.3 MHz, CDCl3) 22.24 (qЈ), 33.79
(tЈ), 60.86 (qЈ), 115.80 (sЈ), 115.91 (tЈ), 125.69 (sЈ), 126.91 (dЈ),
129.61 (sЈ), 136.10 (dЈ), 144.10 (sЈ) and 145.48 (sЈ) (Found: Mϩ,
258.0069. C11H1381BrO2 requires M, 258.0078).
Aldehyde 6 (3.65 g, 15.27 mmol), in a mixture of AcOH (1.33
cm3, 23.23 mmol) and MeOH (150 cm3), was reduced over 10%
Pd–C (1.22 g) at 50 psi for 14 h (Parr shaker). The mixture was
filtered through a pad of Celite (1.5 × 3 cm) and the pad was
washed with MeOH (3 × 10 cm3). Evaporation of the combined
filtrates and flash chromatography of the residue over silica gel
(4 × 15 cm), using 1:3 EtOAc–hexane, gave 7 (2.77 g, 93%) as a
pure (1H NMR, 400 MHz) solid, mp 61–62 ЊC; νmax(CH2Cl2
cast)/cmϪ1 3457, 3373, 2968, 2927, 1760, 1618, 1492, 1475,
1250, 1207 and 1061; δH (400 MHz, CDCl3) 2.16 (s, 3 H), 2.34
(s, 3 H), 3.79 (s, 3 H), 3.84 (br s, 2 H), 6.14 (d, J 7.9, 1 H) and
6.81 (d, J 7.8, 1 H); δC(75.5 MHz, CDCl3) 16.77 (qЈ), 20.51 (qЈ),
59.69 (qЈ), 111.02 (dЈ), 120.85 (sЈ), 124.91 (dЈ), 138.10 (sЈ),
139.15 (sЈ), 141.72 (sЈ) and 168.99 (sЈ) (Found: Mϩ, 195.0895.
C10H13NO3 reqires M, 195.0895).
2-Bromo-3,4-dimethoxy-1-methyl-5-(prop-2-enyl)benzene 11
Me2SO4 (0.78 cm3, 8.25 mmol) was added to a stirred mixture
of 10 (1.766 g, 6.87 mmol), K2CO3 (2.28 g, 16.5 mmol) and dry
acetone (55 cm3). Stirring was continued for 7 h at room tem-
perature and the mixture was then filtered. The insoluble
material was washed with dry acetone and the combined fil-
‡ Phenol 23 is also the precursor to the bromide corresponding to 24
(see ref. 2). The bromide represents the aromatic unit of another cali-
cheamicin (see ref. 1).
1422
J. Chem. Soc., Perkin Trans. 1, 1997

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trates were evaporated. Flash chromatography of the residue
over silica gel (2.5 × 15 cm), using 1:30 EtOAc–hexane, gave 11
(1.72 g, 92%) as a pure (1H NMR, 360 MHz), colourless oil;
νmax(CH2Cl2 cast)/cmϪ1 3077, 2996, 2976, 1639, 1468, 1422,
1391, 1319, 1243, 1069 and 1015; δH (360 MHz, CDCl3) 2.17 (s, 3
H), 3.16 (dt, J 6.5, 1.3, 2 H), 3.91 (s, 3 H), 3.95 (s, 3 H), 5.01–
5.04 (m, 2 H), 5.95–6.00 (m, 1 H) and 6.92 (s, 1 H); δC(50.3
MHz, CDCl3) 22.65 (qЈ), 33.78 (tЈ), 60.23 (qЈ), 60.74 (qЈ), 115.82
(tЈ), 117.84 (sЈ), 126.46 (dЈ), 132.74 (sЈ), 133.82 (sЈ), 136.76 (dЈ),
149.72 (sЈ) and 150.25 (sЈ) (Found: Mϩ, 272.0236. C12H1581BrO2
requires M, 272.0235).
7.41 (s, 1 H) and 10.36 (s, 1 H); δC(75.4 MHz, CDCl3) 18.67 (qЈ),
52.48 (qЈ), 61.59 (qЈ), 62.60 (qЈ), 124.28 (dЈ), 130.35 (sЈ), 131.30
(sЈ), 135.37 (sЈ), 150.25 (sЈ), 153.96 (sЈ), 167.30 (sЈ) and 189.29
(dЈ) (Found: Mϩ, 238.0841. C12H14O5 requires M, 238.0841).
Methyl 4-hydroxy-2,3-dimethoxy-6-methylbenzoate 23
MCPBA (80%; 693 mg, 3.214 mmol) was added to a stirred
solution of 22 (510 mg, 2.143 mmol) in dry CH2Cl2 (8 cm3) and
stirring was continued for 3.5 h. Water (15 cm3) was then added
and the mixture was extracted with Et2O (2 × 20 cm3). The
combined extracts were washed with saturated aqueous
NaHCO3 (2 × 10 cm3) and brine (10 cm3), dried (Na2SO4) and
evaporated. The residue was dissolved in MeOH (6.5 cm3) and
stirred, and 10% aqueous KOH (1.23 cm3) was added to the
resulting solution. After 30 min, the mixture was acidified with
10% aqueous hydrochloric acid and extracted with Et2O (3 × 15
cm3). The combined extracts were washed with water (10 cm3)
and brine (15 cm3), dried (Na2SO4) and evaporated. Flash
chromatography of the residue over silica gel (2 × 20 cm), using
1:4 Et2O–hexane, gave 23 (395 mg, 81%) as a pure (1H NMR,
300 MHz) solid; mp 75–76 ЊC (lit.,2 76 ЊC); νmax(CH2Cl2 cast)/
cmϪ1 3397, 2970, 2941, 1713, 1580, 1467, 1429, 1291, 1197, 1178
and 962; δH (300 MHz, CDCl3) 2.24 (s, 3 H), 3.89 (s, 3 H), 3.91
(s, 6 H), 5.76 (s, 1 H) and 6.56 (s, 1 H); δC(75.4 MHz, CDCl3)
19.39 (qЈ), 52.08 (qЈ), 60.87 (qЈ), 61.28 (qЈ), 112.43 (dЈ), 120.58
(sЈ), 132.42 (sЈ), 137.45 (sЈ), 150.40 (sЈ), 150.52 (sЈ) and 168.13
(sЈ) (Found: Mϩ, 226.0842. C11H14O5 requires M, 226.0841).
Methyl 2,3-dimethoxy-6-methyl-4-(prop-2-enyl)benzoate 12
BunLi (2.5  in hexane; 1.42 cm3, 3.546 mmol) was added
dropwise over ca. 10 min to a stirred and cooled (Ϫ78 ЊC) solu-
tion of 11 (801 mg, 2.955 mmol) in THF (30 cm3). Stirring was
continued for 15 min, and then MeOCOCl (0.34 cm3, 4.432
mmol) in THF (5 cm3) was added dropwise over ca. 5 min.
Stirring was continued for 20 min, the cold bath was removed
and, when the mixture had reached about 0 ЊC, water (10 cm3)
was added. The mixture was extracted with Et2O (2 × 30 cm3)
and the extract was washed with saturated aqueous NaHCO3
(15 cm3) and brine (15 cm3) and dried (Na2SO4). Evaporation of
the solvent and flash chromatography of the residue over silica
gel (2 × 15 cm), using 1:10 Et2O–hexane, gave 12 (596 mg, 81%)
as a pure (1H NMR, 400 MHz), colourless oil; νmax(CH2Cl2
cast)/cmϪ1 2977, 2940, 1733, 1605, 1482, 1459, 1315, 1276 and
1054; δH (300 MHz, CDCl3) 2.22 (s, 3 H), 3.33 (dt, J 6.5, 1.4, 2
H), 3.81 (s, 3 H), 3.88 (s, 3 H), 3.90 (s, 3 H), 5.02–5.05 (m, 2 H),
5.88–5.98 (m, 1 H) and 6.74 (s, 1 H); δC(75.4 MHz, CDCl3)
18.67 (qЈ), 33.84 (tЈ), 51.89 (qЈ), 60.34 (qЈ), 61.00 (qЈ), 115.76
(tЈ), 126.62 (dЈ), 127.38 (sЈ), 130.59 (sЈ), 135.55 (sЈ), 136.62 (dЈ),
148.68 (sЈ), 149.93 (sЈ) and 168.09 (sЈ) (Found: Mϩ, 250.1203.
C14H18O4 requires M, 250.1205).
Methyl 4-hydroxy-3-iodo-5,6-dimethoxy-2-methylbenzoate 24
Phenol 23 was converted into 24 by the literature procedure,2
and was obtained (95%) as a pure (1H NMR, 400 MHz), white
solid; mp 134–135 ЊC (lit.,2 134–135 ЊC); νmax(CH2Cl2 cast)/cmϪ1
3375, 2994, 2944, 2837, 1714, 1563, 1462, 1420, 1268, 1217,
1095, 1064 and 998; δH (400 MHz, CDCl3) 2.35 (s, 3 H), 3.87 (s,
3 H), 3.91 (s, 3 H), 3.92 (s, 3 H) and 6.31 (br s, 1 H); δC(75.4
MHz, CDCl3) 25.21 (qЈ), 52.42 (qЈ), 61.02 (qЈ), 61.33 (qЈ), 84.00
(sЈ), 121.75 (sЈ), 134.05 (sЈ), 136.56 (sЈ), 149.61 (sЈ), 150.47 (sЈ)
and 167.79 (sЈ); (Found: Mϩ, 351.9801. C11H13IO5 requires M,
351.9807).
Methyl (Z)- and (E)-2,3-dimethoxy-6-methyl-4-(prop-1-enyl)-
benzoate 21
RhCl3ؒ3H2O (33 mg, 0.125 mmol) was added to a solution of
12 (403 mg, 1.61 mmol) in dry EtOH (3 cm3) and the mixture
was stirred at 70 ЊC for 8 h. The solvent was then evaporated
and the residue was diluted with Et2O (30 cm3), washed with
water (2 × 10 cm3) and brine (10 cm3), dried (Na2SO4) and
evaporated. Flash chromatography of the residue over silica gel
(2 × 15 cm), using 1:20 EtOAc–hexane, gave 21 (359 mg, 89%)
as a pure (1H NMR, 300 MHz), colourless oil, which was a 9:1
mixture of E and Z isomers; νmax(CH2Cl2 cast)/cmϪ1 3034, 2994,
2939, 1732, 1602, 1458, 1448, 1405, 1277, 1154 and 1062; δH (300
MHz, CDCl3) [major (E) isomer only] 1.91 (dd, J 6.6, 1.6, 3 H),
2.24 (s, 3 H), 3.80 (s, 3 H), 3.88 (s, 3 H), 3.91 (s, 3 H), 6.37 (dq, J
16.3, 6.6, 1 H), 6.61 (dq, J 15.8, 1.4, 1 H) and 7.00 (s, 1 H);
δC(75.4 MHz, CDCl3) [major (E) isomer only] 18.82 (qЈ), 18.98
(qЈ), 52.02 (qЈ), 60.62 (qЈ), 61.31 (qЈ), 122.62 (dЈ), 124.60 (dЈ),
127.34 (sЈ), 128.33 (dЈ), 130.79 (sЈ), 133.56 (sЈ), 147.73 (sЈ),
150.39 (sЈ) and 168.15 (sЈ) (Found: Mϩ, 250.1203. C14H18O4
requires M, 250.1205).
Methyl 6-formyl-2,3-(methylenedioxy)benzoate 15
Piperonal was converted into its cyclohexyl imine (14) by the
literature procedure.7 The crude material (97%) was of
adequate purity (1H NMR, 300 MHz) for use directly in the
next step, for which the literature procedure7 was modified
slightly. BunLi (2.5  in hexane; 8.20 cm3, 20.5 mmol) was
added dropwise over ca. 10 min to a stirred and cooled
(Ϫ78 ЊC) solution of the crude imine (4.32 g, 18.7 mmol) in
THF (150 cm3). Stirring was continued for 15 min, and then
MeOCOCl (2.89 cm3, 37.4 mmol) in THF (30 cm3) was added
dropwise over 10 min. Stirring was continued for 10 min, the
cold bath was removed and, when the mixture had reached
room temperature, 15% aqueous hydrochloric acid (15 cm3) was
added. Stirring was continued for 1 h and then the mixture was
concentrated to remove the THF and the residue was extracted
with Et2O (2 × 80 cm3). The combined extracts were washed
with water (2 × 20 cm3), saturated aqueous NaHCO3 (2 × 15
cm3) and brine (20 cm3) and dried (Na2SO4). Evaporation of the
solvent and flash chromatography of the residue over silica gel
(4 × 25 cm), using 2:3 Et2O–hexane, gave 15 (3.42 g, 88%) as a
pure (1H NMR, 400 MHz), white solid; mp 104–105 ЊC (lit.,7
105.5–106.5 ЊC).
Methyl 4-formyl-2,3-dimethoxy-6-methylbenzoate 22
OsO4 (2.5% w/v in ButOH; 2.10 cm3, 0.34 mmol) was added to a
stirred mixture of 21 (710 mg, 2.84 mmol), ButOH (10 cm3),
CCl4 (20 cm3) and water (20 cm3). After 15 min, NaIO4 (1.52 g,
7.10 mmol) was added in one portion, and stirring was con-
tinued for 2 h. Water (20 cm3) was then added and the mixture
was extracted with Et2O (2 × 30 cm3). The combined extracts
were washed with water (20 cm3), 10% aqueous NaHSO3 (20
cm3) and brine (15 cm3), dried (Na2SO4) and evaporated. Flash
chromatography of the residue over silica gel (2 × 18 cm), using
1:5 Et2O–hexane, gave 22 (562 mg, 83%) as a pure (1H NMR,
400 MHz), white solid; mp 49–50 ЊC; νmax(CH2Cl2 cast)/cmϪ1
2949, 1735, 1692, 1466, 1439, 1280, 1052 and 990; δH (400 MHz,
CDCl3) 2.27 (s, 3 H), 3.91 (s, 3 H), 3.95 (s, 3 H), 3.98 (s, 3 H),
Methyl 6-methyl-2,3-(methylenedioxy)benzoate 16
Aldehyde 15 (1.54 g, 74.0 mmol) in a mixture of AcOH (0.6
cm3) and MeOH (74 cm3) was reduced over 10% Pd–C (592 mg)
at 50 psi for 9 h (Parr shaker). The mixture was filtered through
a pad of Celite (1 × 4 cm) and the pad was washed with MeOH
(3 × 10 cm3). Evaporation of the combined filtrates and flash
chromatography of the residue over silica gel (3 × 15 cm), using
J. Chem. Soc., Perkin Trans. 1, 1997
1423

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1:7 EtOAc–hexane, gave 16 (1.33 g, 93%) as a pure (1H NMR,
400 MHz), white solid; mp 70–71 ЊC; νmax(CH2Cl2 cast)/cmϪ1
2968, 2953, 1724, 1626, 1470, 1457, 1271, 1127 and 1057; δH (400
MHz, CDCl3) 2.42 (s, 3 H), 3.91 (s, 3 H), 6.01 (s, 2 H), 6.67 (dd,
J 7.9, 0.7, 1 H) and 6.79 (d, J 7.9, 1 H); δC(50.3 MHz, CDCl3)
20.74 (qЈ), 51.88 (qЈ), 101.59 (tЈ), 110.65 (dЈ), 113.62 (sЈ), 123.45
(dЈ), 131.81 (sЈ), 146.21 (sЈ), 147.99 (sЈ) and 165.90 (sЈ) (Found:
Mϩ, 194.0578. C10H10O4 requires M, 194.0579).
(sЈ), 129.31 (sЈ), 133.17 (dЈ), 146.60 (sЈ), 149.43 (sЈ) and 168.33
(sЈ) (Found: Mϩ, 236.1048. C13H16O4 requitres M, 236.1048).
Methyl 3-hydroxy-2-methoxy-6-methyl-4-(prop-2-enyl)benzoate
20
A solution of 19 (110 mg, 0.466 mmol) in decalin (0.8 cm3) was
refluxed for 8 h under Ar and then cooled to room temperature.
Flash chromatography of the mixture (without evaporation)
over silica gel (1.5 × 15 cm), using 1:3 Et2O–hexane, gave 20
(95.2 mg, 86%) as a pure (1H NMR, 400 MHz), colourless oil;
νmax(CH2Cl2 cast)/cmϪ1 3445, 3002, 2977, 2950, 1728, 1614,
1486, 1460, 1434, 1279 and 1195; δH (400 MHz, CDCl3) 2.23 (s,
3 H), 3.37 (dt, J 6.4, 1.2, 2 H), 3.83 (s, 3 H), 3.92 (s, 3 H), 5.06–
5.11 (m, 2 H), 5.60 (s, 1 H), 5.92–6.02 (m, 1 H) and 6.73 (s, 1 H);
δC(50.3 MHz, CDCl3) 18.98 (qЈ), 34.00 (tЈ), 52.21 (qЈ), 62.18
(qЈ), 116.00 (tЈ), 124.68 (sЈ), 126.98 (dЈ), 127.25 (sЈ), 128.68 (sЈ),
135.94 (dЈ), 144.27 (sЈ), 144.54 (sЈ) and 168.16 (sЈ) (Found: Mϩ,
236.1047. C13H16O4 requires M, 236.1048).
Methyl 2,3-dihydroxy-6-methylbenzoate 17
Ester 16 (1.01 g, 5.20 mmol) was added in one portion to a
stirred and cooled (0 ЊC) mixture of AlBr3 (5.55 g, 20.8 mmol)
in EtSH (24 cm3) contained in a one-necked round-bottomed
flask fitted with a drying tube (CaSO4), and stirring at 0 ЊC was
continued for 1 h. The mixture was poured into water (20 cm3),
acidified with 10% hydrochloric acid and extracted with Et2O
(3 × 20 cm3). The combined extracts were washed with water
(2 × 15 cm3) and brine (15 cm3), dried (Na2SO4) and evapor-
ated. Flash chromatography of the residue over silica gel
(3 × 15 cm), using 1:5 EtOAc–hexane, gave 17 (880 mg, 93%) as
a pure (1H NMR, 300 MHz), white solid; mp 104–105 ЊC;
νmax(CH2Cl2 cast)/cmϪ1 3478, 1659, 1597, 1445, 1293, 1274 and
799; δH (300 MHz, CDCl3) 2.46 (s, 3 H), 3.97 (s, 3 H), 5.61 (s, 1
H), 6.63 (d, J 8.3, 1 H), 6.97 (d, J 8.2, 1 H) and 11.59 (s, 1 H);
δC(50.3 MHz, CDCl3) 23.20 (qЈ), 52.23 (qЈ), 111.77 (sЈ), 118.48
(dЈ), 122.12 (dЈ), 131.40 (sЈ), 143.20 (sЈ), 149.94 (sЈ) and 172.36
(sЈ) (Found: Mϩ, 182.0580. C9H10O4 requires M, 182.0579).
Methyl 2,3-dimethoxy-6-methyl-4-(prop-2-enyl)benzoate 12
Me2SO4 (0.21 cm3, 2.217 mmol) was added to a stirred mixture
of 20 (436 mg, 1.847 mmol), K2CO3 (600 mg, 4.34 mmol) and
dry acetone (20 cm3). Stirring was continued for 8 h and the
mixture was then filtered. The insoluble material was washed
with dry acetone and the combined filtrates were evaporated.
Flash chromatography of the residue over silica gel (2 × 15 cm),
using 1:10 Et2O–hexane, gave 12 (448 mg, 97%) as a pure (1H
NMR, 300 MHz), colourless oil, identical with material made
from vanillin, as described above.
Methyl 3-hydroxy-2-methoxy-6-methylbenzoate 18
MeI (1.12 cm3, 17.97 mmol) was added to a stirred mixture of
17 (1.09 g, 5.99 mmol) and Li2CO3 (1.33 g, 17.97 mmol) in dry
DMF (15 cm3) and stirring was continued for 4 days. The mix-
ture was poured into water (30 cm3), acidified with 10% hydro-
chloric acid and extracted with Et2O (3 × 20 cm3). The com-
bined extracts were washed with water (2 × 15 cm3) and brine
(15 cm3), dried (Na2SO4) and evaporated. Flash chroma-
tography of the residue over silica gel (3 × 20 cm), using 1:4
EtOAc–hexane, gave 18 (585 mg, 50%; 71% after allowing for
recovered starting material) as a pure (1H NMR 300 MHz),
colourless oil, methyl 2-hydroxy-6-methyl-3-methoxybenzoate
(199 mg, 17%; 24% after allowing for recovered starting
material), also as a pure (1H NMR, 300 MHz), colourless oil,
and recovered 17 (324 mg, 30%). Phenol 18 had; νmax(CH2Cl2
cast)/cmϪ1 3387, 3951, 2925, 1731, 1663, 1487 and 1272; δH (300
MHz, CDCl3) 2.25 (s, 3 H), 3.84 (s, 3 H), 3.93 (s, 3 H), 5.51 (br s,
1 H), 6.86 (d, J 7.9, 1 H) and 6.92 (d, J 8.0, 1 H); δC(50.3 MHz,
CDCl3) 18.70 (qЈ), 52.28 (qЈ), 62.02 (qЈ), 117.19 (dЈ), 126.26
(dЈ), 127.32 (sЈ), 127.63 (sЈ), 144.23 (sЈ), 146.63 (sЈ) and 168.30
(sЈ) (Found: Mϩ, 196.0734. C10H12O4 requires M, 196.0735).
Acknowledgements
We thank the NSERC and the Alberta Cancer Board for finan-
cial support.
References
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8 Cf. S. V. Kessor, P. Singh, R. Vohra, R. Nachhattar, P. Kanr and
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13 D. L. J. Clive, S. M. Magnuson, H. W. Manning and D. L. Mayhew,
J. Org. Chem., 1996, 61, 2095.
Methyl 2-methoxy-6-methyl-3-(prop-2-enyloxy)benzoate 19
Allyl bromide (0.27 cm3, 3.214 mmol) was added to a stirred
mixture of 18 (525 mg, 2.678 mmol), anhydrous K2CO3 (888
mg, 6.418 mmol) and dry acetone (15 cm3). The mixture was
refluxed with stirring for 7 h, cooled to room temperature and
diluted with water (20 cm3). The mixture was extracted with
Et2O (3 × 20 cm3) and the combined extracts were washed with
water (15 cm3) and brine (15 cm3), dried (Na2SO4) and evapor-
ated. Flash chromatography of the residue over silica gel
(2.5 × 12 cm), using 1:10 EtOAc–hexane, gave 19 (582 mg,
92%) as a pure (1H NMR, 400 MHz), colourless oil; νmax
-
(CH2Cl2 cast)/cmϪ1 2992, 2949, 1732, 1580, 1490, 1461, 1433,
1297, 1271, 1143 and 1068; δH (400 MHz, CDCl3) 2.22 (s, 3 H),
3.88 (s, 3 H), 3.91 (s, 3 H), 4.56 (dt, J 5.2, 1.6, 2 H), 5.26 (dq, J
10.5, 1.4, 1 H), 5.28 (dq, J 17.2, 1.6, 1 H), 6.01–6.10 (m, 1 H)
and 6.85 (s, 2 H); δC(75.4 MHz, CDCl2) 18.47 (qЈ), 52.07 (qЈ),
61.40 (qЈ), 69.88 (tЈ), 115.78 (dЈ), 117.44 (tЈ), 125.33 (dЈ), 127.93
Paper 6/05837J
Received 22nd August 1996
Accepted 18th November 1996
1424
J. Chem. Soc., Perkin Trans. 1, 1997