5800 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 19
McLean et al.
1
as fine yellow needles: mp 105-107 °C. H NMR (300 MHz,
(d, 1 H, vinyl CH2), 4.45 (d, 2 H, OCH2CH), 3.63 (s, 3 H, OMe);
low-resolution CIMS, m/z (rel intensity) 252/254 (MH+, 51/49).
4-(5-Methoxy-2,3-dihydrobenzofuran-3-yl)butanoic Acid ((()-
20). The procedure of Togo et al.24 was employed. In a 2 L, four-
necked resin kettle with mechanical stirrer, addition funnel, and
reflux condenser with argon inlet was placed 19 (50 g, 205 mmol)
dissolved in 800 mL of benzene. The solution was purged with
argon for 15 min and then heated to reflux. A solution of tributyltin
hydride (75 g, 257 mmol) dissolved in 200 mL of dry benzene
was sparged with argon and then placed into the addition funnel.
Ethyl acrylate was added by syringe in one portion to the boiling
solution. AIBN (3 g, 18 mmol) dissolved in 10 mL of benzene
was then added dropwise in four portions over 1 h, while the
tributyltin hydride solution was added dropwise over the same time
period. Upon complete addition of the tributyltin hydride, the
mixture was heated at reflux for an additional hour and then allowed
to cool to room temperature. The solution was transferred to a 1000
mL round-bottomed flask, and the benzene was removed under
reduced pressure to yield a clear oil. This oil was dissolved in 600
mL of MeOH, and 200 mL of 3 N aqueous KOH was added. The
mixture was left stirring overnight at room temperature. The MeOH
was removed under reduced pressure, and 300 mL of H2O was
added. The alkaline aqueous solution was washed with 2 × 100
mL of Et2O, then acidified to pH 1 with concentrated H2SO4,
resulting in the formation of a cloudy suspension. The mixture was
extracted with 3 × 100 mL of Et2O, and the ether extracts were
washed with 1 N HCl and brine, then dried over anhydrous Na2-
SO4. Evaporation of the ether afforded 4-(5-methoxy-2,3-dihy-
drobenzofuran-3-yl)butanoic acid (41.4 g, 85%) as a viscous off-
white oil that solidified overnight under vacuum. An analytical
sample was recrystallized from EtOAc/hexanes (mp 70-71 °C).
Smaller runs provided yields up to 96%: mp 70-71 °C. 1H NMR
(300 MHz, CDCl3) δ 6.71 (s, 1 H, ArH), 6.56 (d, J ) 2 Hz, 2 H,
ArH × 2), 4.47 (t, J ) 9 Hz, 1 H, OCH2), 4.03 (dd, J ) 7 Hz, 2
Hz, 1 H, OCH2), 3.58 (s, 3 H, OMe), 3.29 (m, 1 H, ArCH), 2.15
(t, J ) 9 Hz, 2 H, CH2CO2H), 1.61 (m, 1 H, CHCH2), 1.43 (m, 3
H, CHCH2CH2); low-resolution CIMS, m/z (rel intensity) 237
(MH+, 100). Anal. (C13H16O4) C, H.
CDCl3) δ 7.16 (t, J ) 2 Hz, 1 H, ArCCH), 6.74 (d, J ) 9 Hz, 1 H,
ArH), 6.69 (d, J ) 9 Hz, 1 H, ArH), 3.83 (s, 3 H, OCH3), 3.78 (s,
1 H, OCH3), 3.47 (d, J ) 2 Hz, 2 H, ArCH2); low-resolution CIMS,
m/z (rel intensity) 202 (M + H, 100). Anal. (C12H11NO2) C, H, N.
C-(4,7-Dimethoxyindan-1-yl)methylamine Hydrochloride ((()-
16). Unsaturated nitrile 15 (0.25 g, 1.24 mmol) dissolved in absolute
EtOH (250 mL) was placed in a 500 mL glass Parr hydrogenation
flask containing 200 mg of 10% Pd/C and shaken for 20 min under
20 psi of H2. The solution was filtered through diatomaceous earth
to remove the catalyst and then placed back into the hydrogenation
flask along with 1 g of activated Raney nickel 2800. Ammonia
gas was bubbled through the solution for 1 min, and the flask was
then shaken under 45 psi of H2 for 6 h. The catalyst was removed
by filtration through diatomaceous earth and the solvent was
evaporated to yield a clear oil that was acidified with 1 N methanolic
HCl and evaporated to yield (()-16 hydrochloride (0.29 g, 97%)
as a white solid. An analytical sample was recrystallized from 95%
EtOH: mp 144-146 °C. 1H NMR (free base, 300 MHz, CDCl3) δ
6.53 (s, 2 H, 2 × ArH), 3.68 (s, 3 H, OCH3), 3.66 (s, 3 H, OCH3),
3.32-3.24 (m, 1 H, ArCH), 2.95-2.72 (m, 4 H, CH2NH2 and
ArCH2), 2.17-2.06 (m, 1 H, ArCHCH2CH2), 1.90-1.81 (m, 1 H,
ArCHCH2CH2); low-resolution CIMS, m/z (rel intensity) 208 (M
+ H, 100). Anal. (C12H18ClNO2‚1/3H2O) C, H, N.
C-(5-Bromo-4,7-dimethoxyindan-1-yl)methylamine Hydro-
chloride ((()-3). Amine free base (()-16 (0.29 g, 0.85 mmol) was
dissolved in glacial AcOH (15 mL) with stirring. Br2 (0.14 g, 0.87
mmol) dissolved in 3 mL of glacial AcOH was added dropwise
over 1 min, and the mixture was stirred in the dark for 20 min.
Et2O (40 mL) was added, and the resulting precipitate was collected
by suction filtration. This solid was dissolved in a minimum of
H2O and basified to pH 11 with 2 N aqueous NaOH. The mixture
was extracted with 3 × 30 mL of CH2Cl2, and the organic extracts
were combined and evaporated to afford an oil. Neutralization of
the free base with 1 N methanolic HCl and evaporation gave (()-3
hydrochloride (0.21 g, 75%) as an off-white powder. The salt was
recrystallized from MeOH/EtOAc to afford a white powder: mp
1
231-233 °C. H NMR (300 MHz, D2O) δ 7.11 (s, 1 H), 3.75 (s,
5-Methoxy-7,8,9,9a-tetrahydro-1H-2-oxabenzo[cd]azulen-6-
one ((()-21). Following the procedure of Hellwinkel and Kosack,32
carboxylic acid (()-20 (22.5 g, 95.2 mmol) was dissolved in
trifluoroacetic acid (350 mL) with stirring at room temperature.
Trifluoroacetic anhydride (60 mL) was then added, and the solution
was stirred for another hour at room temperature, followed by 6 h
at reflux. After allowing the solution to cool to room temperature,
it was poured onto crushed ice (500 g) and the aqueous mixture
was extracted with 3 × 150 mL of CH2Cl2. The organic extracts
were washed with 1 N aqueous NaOH solution until the washes
became basic, and then the organic phase was washed with H2O,
dried over anhydrous Na2SO4, filtered, and evaporated to give the
product as a brown solid. Recrystallization twice from hexanes gave
the product (()-21 (7.1 g, 34%) as a light-yellow solid: mp 62-
3 H), 3.74 (s, 3 H), 3.67 (m, 1 H), 3.21 (dd, J ) 6 Hz, 1 H), 3.07
(dd, J ) 7 Hz, 1 H), 2.75 (t, J ) 7 Hz, 2 H), 2.30 (m, 1 H), 1.89
(m, 1 H); low-resolution ESIMS, m/z (rel intensity) 286/288 (M +
H, 100). Anal. (C11H15Br2NO2) C, H, N.
2-Bromo-4-methoxyphenol (18). Following the procedure of
Chambers,6 p-methoxyphenol 17 (200 g, 1.61 mol) was dissolved
in 1 L of MeOH in a 2 L flask fitted with an addition funnel and
magnetic stirrer. The flask was cooled to 0 °C, and Br2 (284 g,
1.78 mol) was added dropwise with stirring. Upon complete addition
of the bromine, the mixture was allowed to warm to room temp
and was stirred overnight. The MeOH was evaporated under
reduced pressure, and the residue was purified by short path
distillation at water aspirator pressure. The fraction distilling at
125-135 °C was collected and allowed to solidify, providing a
solid mass of needle-like crystals (241 g, 73%): bp 130 °C (25
1
63 °C. H NMR (300 MHz, CDCl3) δ 6.72 (d, J ) 9 Hz, 1 H,
ArH), 6.65 (d, J ) 9 Hz, 1 H, ArH), 4.67 (t, J ) 9 Hz, 1 H, OCH2),
4.00 (dd, J ) 9 Hz, 1 Hz, 1 H, OCH2), 3.72 (s, 3 H, OMe), 3.60
(m, 1 H, ArCH), 2.10-1.58 (m, 4 H, CCH2CH2CH); low-resolution
CIMS, m/z (rel intensity) 219 (MH+, 100). Anal. (C13H14O3) C, H.
5-Methoxy-1,8,9,9a-tetrahydro-2-oxabenzo[cd]azulene-6-car-
bonitrile ((()-22). Trimethylsilyl cyanide (0.80 g 1.10 mL, 8.0
mmol) dissolved in 10 mL of CH2Cl2 was added dropwise under
argon to a stirred solution of ketone (()-21 (1.35 g, 6.19 mmol)
and ZnI2 (100 mg, 0.31 mmol) in 100 mL of CH2Cl2. The mixture
was heated at reflux for 6 h and then allowed to cool to room temp.
The solvent was evaporated, and the residue was redissolved in
100 mL of toluene. Amberlyst-15 acidic resin (1 g) was added,
and the flask was fitted with a Dean-Stark trap and reflux
condenser, and the mixture was heated at reflux for 3 h. The resin
was removed by filtration through diatomaceous earth, and the filter
cake was washed with toluene. The filtrate was treated with a
mixture of activated carbon and MgSO4 to decolorize it, then filtered
again through diatomaceous earth and evaporated under reduced
1
mmHg). H NMR (300 MHz, CDCl3) δ 7.00 (d, J ) 3 Hz, 1 H,
ArH), 6.92 (d, J ) 8.9 Hz, 1 H, ArH), 6.78 (dd, J ) 8.9, 3.0 Hz,
1 H, ArH), 5.18 (bs, 1 H, OH), 3.72 (s, 3 H, OMe); low-resolution
CIMS, m/z (rel intensity) 202/204 (MH+, 51/49).
4-Allyloxy-3-bromoanisole (19). Following the procedure of
Green,23 2-bromo-4-methoxyphenol 18 (60 g, 295 mmol) and allyl
bromide (40 g, 310 mmol) were dissolved in 600 mL of acetone in
a mechanically stirred round-bottomed flask containing K2CO3 (200
g, 1.44 mol). The mixture was heated at reflux overnight, allowed
to cool, and filtered to remove solids. The acetone was removed
by rotary evaporation, and the residue was dissolved in 500 mL of
Et2O and washed with 2 × 150 mL each of 2 N aqueous NaOH
and brine. The ether layer was dried over anhydrous Na2SO4,
filtered, and evaporated to yield a brown oil. Kugelrohr distillation
provided a water white oil (67.69 g, 94%): bp 90 °C (0.05 Torr).
1H NMR (300 MHz, CDCl3) δ 7.03 (s, 1 H, ArH), 6.70 (dd, 2 H,
ArH × 2), 5.96 (m, 1 H, vinyl CH), 5.35 (d, 1H, vinyl CH2), 5.25