4442 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 21
Zacheis et al.
[HOCdO]; MS (EI) calcd for C22H25O3SN [M+] 383.1555, found
381.1552. Anal. (C22H25O3SN) C, H, N.
[Ar-C]; MS (EI) calcd for C15H22O2 [M+] 234, found 234. The
sample of 25 was used at once to prepare 9.
2-(3-Meth oxyp h en yl)-2-m eth ylp r op a n en itr ile (27). An
orange mixture of KOH (20.0 g. 0.356 mol), triethylbenzylam-
monium bromide (TEBA; 2.0 g, 7.46 mmol), and (3-methoxy-
phenyl)acetonitrile (26; 20.0 g, 0.135 mol) was heated at 80
°C for 0.5 h. Methyl iodide (11.50 g, 0.810 mol) was added
slowly over 2 h, and the resulting yellow mixture was heated
(80 °C) for 1 h. Additional KOH (20.0 g, 0.356 mol) was then
added along with TEBA (2.0 g, 7.46 mmol), and the new
mixture was stirred vigorously for 0.5 h. Methyl iodide (11.50
g, 0.081 mol) was added over 1 h, and the resulting mixture
was stirred with heating (80-100 °C) for 5 h. After cooling to
rt, the reaction mixture was extracted (toluene, 5 mL). The
combined organic extracts were washed with water and brine
and then dried (MgSO4). Evaporation of the solvent gave an
oil (3.8 g, 84%) which was vacuum distilled (100-101 °C/∼2
mmHg) to a colorless oil (13.4 g, 57%) of 27: IR (neat) 2242
CtN cm-1; 1H NMR (DCCl3) δ 1.72 [s, 6 H, (H3C)2], 3.83 [s, 3
H, OCH3], 6.84 [2d 1 H, Ar-H], 7.01 [t, 1 H, Ar-H], 7.05 [2d,
1 H, Ar-H], 7.31 [t, 1 H, Ar-H]; 13C NMR (DCCl3) ppm 29.08
[(H3C)2], 36.76 [Ar-C(CH3)2], 55.30 [ArOCH3], 111.40-159.87
[Ar-C], 123.44 [CtN]; MS (EI) calcd for C11H13NO [M+] 175,
found 175. This sample of 27 was used to prepare 28.
N-(4-Meth oxyoxop h en yl)-4,4-d im eth yl-3,4-d ih yd r o-2H-
ben zo[b]p yr a n -6-ylh yd r oxa m ic Acid (21). Acid 207 (0.300
g, 1.40 mmol) and thionyl chloride (15 mL) were stirred at rt
for 16 h. Excess thionyl chloride was evaporated under
aspirator pressure, and the residual acid choride (an oil) was
further dried under higher vacuum (∼2 mmHg) to remove
traces of thionyl chloride. The hydroxylamine (0.253 g, 1.40
mmol) was dissolved in THF (10 mL), and then NaHCO3 (0.176
g, 2.1 mmol) was added at rt. The above acid chloride was
dissolved in a minimum of dry ether and then was added
slowly to the solution of the hydroxylamine at 0 °C. The
resulting mixture was stirred (rt) for 18 h, filtered, and
evaporated in vacuo to yield a solid. Chromatography of the
solid (hexanes:EtOAc, 1:10) gave 21 (0.250 g, 50%): mp 70-
71 °C; IR (KBr) 3428 (O-H), 1721, 1634 (CdO) cm-1; 1H NMR
(DCCl3) δ 1.13 [s, 6 H, (CH3)2], 1.78 [t, 2 H, J ) 5.6 Hz, CCH2)]
3.90 [s, 3 H, OCH3], 4.19 [t, 2 H, J ) 5.6 Hz, H2CO], 6.68 [d,
2 H, Ar-H], 7.20 [dd, 1 H, Ar-H], 7.25 [dd, 1 H, Ar-H], 7.34
[d, 1 H, Ar-H], 7.96 [d, 2 H, Ar-H], 9.18 [s, 1 H, OH]. Anal.
(C20H21NO5) C, H. Acid 21 was used at once to obtain 7.
2,3-Dih yd r o-2,6-d ih yd r oxy-2,4,4,5,7-p en t a m et h yl-2H -
ben zop yr a n (23). To a solution of 1.50 mL (4.50 mmol) of 3
M methylmagnesium bromide in ether (5 mL) was added (rt)
the coumarol 2227 (0.100 g, 0.45 mmol) in ether (5 mL). The
resulting solution was stirred for 48 h (rt). After the solution
was allowed to cool to rt, a saturated solution (∼10 mL) of
aqueous H4NCl was added slowly. Separation of the layers was
followed by extraction (ether, 3 × 10 mL) of the organic layer
to give extracts which were washed with water and brine. After
drying (MgSO4), the solution was evaporated to give the lactol
23 as a colorless solid (0.57 g, 54%): mp 105.5-106.5 °C; IR
2-(3-Meth oxyp h en yl)-2-m eth ylp r op a n oic Acid (28). A
mixture of 27 (3.8 g, 0.0217 mol), KOH (5.00 g, 0.089 mol),
diethylene glycol (30 mL), and water (5 mL) were heated at
130-140 °C for 3 days and turned brown. After cooling to rt,
the solution was poured into cold water. Extraction (benzene,
8 × 40 mL) of the aqueous layer followed, and then the residual
aqueous layer was made acidic (concd HCl, pH ∼ 3). The new
aqueous layer was extracted (ether, 4 × 30 mL), and the
combined extracts were dried (MgSO4). Evaporation of the
solvent gave a yellow solid which recrystallized (hexane) to a
white solid 28 (3.81 g, 69%): mp 79-80 °C (lit.28 mp 80-81.5
°C). Since spectral data were scarce on 28, the following data
1
(KBr) 3472, 3408 (O-H) cm-1 ; H NMR (DCCl3) δ 1.41 [s, 3
H, CCH3], 1.58 [s, 3 H, CCH3], 1.62 [s, 3 H, C(OH)-CH3], 1.90
[d, 1 H, J ) 14 Hz, CH2], 1.99 [d, 1 H, J ) 14 Hz, CH2], 2.18
[s, 3 H, Ar-CH3], 2.38 [s, 3 H, Ar-CH3], 4.31 [s, 1 H, OH],
6.52 [s, 1 H, Ar-H]; 13C NMR (DCCl3) ppm 14.75 [Ar-CH3],
15.86 [Ar-CH3], 28.92 [(H3C)2], 29.95 [(H3C)2], 30.93 [CH2],
32.14 [C(CH3)2], 50.07 [H3C(COAr)], 95.79 [C(OH)], 117.34-
147.25 [Ar-C]. MS (EI) calcd for C14H20O3 [M+] 236, found 236.
Lactol 23 was converted to 24.
were taken: IR (KBr) 3434-2538 (CO2H), 1702 (CdO) cm-1
;
1H NMR (DCCl3) δ 1.58 [s, 6 H, (H3C)2], 3.80 [s, 3 H, ArOCH3],
6.80 [ddd, 1 H, Ar-H], 6.95 [t, 1 H, Ar-H], 6.99 [ddd, 1 H,
Ar-H], 7.25 [t, 1 H, Ar-H]; MS (EI) calcd for C11H14O3 [M+]
194, found 194. Acid 28 was converted directly to 29.
2-(3-Meth oxyp h en yl)-2-m eth yl-1-p r op a n ol (29). To a
mixture of LiAlH4 (2.23 g, 58.9 mmol) in dry THF (19 mL)
was added dropwise acid 28 (3.81 g, 19.6 mmol) in dry THF
(5 mL) over 0.5 h. After being heated at reflux (48 h), the
resulting mixture was allowed to cool to rt and was then
treated cautiously with ethanol/water to destroy residual
LiAlH4. A white solid formed and was filtered, and the
remaining aqueous layer was extracted (ether, 5 × 30 mL).
The combined extracts were washed with brine, dried (MgSO4),
and evaporated to a colorless oil 29 (2.6 g, 75%): IR (neat)
6-Hydr oxy-2,4,4,5,7-pen tam eth yl-4H-1-ben zopyr an (24).
A mixture of lactol 23 (0.100 g, 0.42 mmol), a catalytic amount
of p-toluenesulfonic acid (0.025 g), 4A molecular sieves (1.0
g), and toluene was boiled for 2 h. After cooling to rt and
filtering, the filtrate was washed with a saturated solution of
NaHCO3 (∼10 mL) and then with brine. The dried (Na2SO4)
organic solution was evaporated to yield 24 (0.082 g, 89%) as
a light yellow oil: IR (neat) 3576 (O-H) cm-1; 1H NMR (DCCl3)
δ 1.43 [s, 6 H, (H3C)2)], 1.85 [s, 3 H, CdC-CH3], 2.19 [s, 3 H,
Ar-CH3], 2.33 [s, 3 H, Ar-CH3], 4.33 [s, 1 H, OH], 4.39 [s, 1
H, CdCH2], 6.60 [s, 1 H, Ar-H]; 13C NMR (DCCl3) ppm 14.38
[Ar-CH3], 15.79 [Ar-CH3], 18.87 [CdCCH2], 31.82 [(H3C)2],
32.42 [C(CH3)2], 108.74 [CdCH], 116.12 [CdCCH3], 121.91-
148-30 [Ar-C]; MS (EI) calcd for C14H18O2 [M+] 218, found
218. This chromenol 24 was used directly to prepare hetero-
arotinoid 8.
3392 (O-H) cm-1 1H NMR (DCCl3) δ 1.32 [s, 6 H, (H3C)2],
;
3.59 [s, 2 H, H2COH], 3.81 [s, 3 H, ArOCH3], 6.75 [2 d, 1 H,
Ar-H], 6.93 [t, 1 H, Ar-H], 6.97 [2 d, 1 H, Ar-H], 7.27 [t, 1
H, Ar-H]; MS (EI) calcd for C11H16O2 [M+] 180, found 180.
The sample of 29 was used immediately to prepare ether 30.
1,1,4,4-Tetr a m eth yl-6-m eth oxy-3,4-d ih yd r o-1H-2-ben -
zop yr a n (30). A solution of alcohol 29 (0.989 g, 5.6 mmol),
acetone (30 mL), and concd HCl (10 mL) was heated and
stirred at 45-50 °C for 2 h and at rt for 12 h. The deep yellow
solution was allowed to cool to rt and was then poured into
ice-water. Two layers were separated, and the organic layer
was extracted (ether, 5 × 20 mL). The combined extracts were
washed with water (30 mL), saturated NaHCO3 (30 mL), and
brine and then was dried (MgSO4). Evaporation of the solvent
gave a colorless oil 30 (0.92 g, 75%) which was used directly
to prepare 31. Spectral data for 30 were as follows: 1H NMR
(DCCl3) δ 1.26 [s, 6 H, (H3C)2], 1.51 [s, 6 H, (H3C)2], 3.58 [s, 2
H, H2CO], 3.80 [s, 3 H, ArOCH3], 6.73 [dd, 1 H, Ar-H], 6.82
[d, 1 H, Ar-H], 6.99 [d, 1 H, Ar-H]; MS (EI) calcd for C14H20O2
[M+] 220, found 220.
2,2,4,4,5,7-Hexa m eth yl-6-h yd r oxy-3,4-d ih yd r o-2H-ben -
zo[b]p yr a n (25). To a solution of methylmagnesium bromide
(1.50 mL, 34.50 mmol, 3 M) in THF (5 mL) was added
coumarol 2227 (0.100 g, 0.45 mmol) in THF (5 mL) at rt. The
resulting solution was stirred for 4 days at reflux and was then
allowed to cool. Saturated aqueous H4NCl was added, and two
layers separated. Extraction (ether, 3 × 10 mL) of the aqueous
layer and combining the extracts gave an organic solution
which was washed with H2O and brine. The dried (MgSO4)
solution was evaporated to a colorless solid (0.086 g, 76%) of
25: mp 62.5-64.5 °C; IR (KBr) 3458 (O-H) cm-1 1H NMR
;
(DCCl3) δ 1.31 [s, 6 H, (H3C)2], 1.47 [s, 6 H, (H3C)2], 1.84 [s, 2
H, CH2], 2.17 [s, 3 H, Ar-CH3], 2.37 [s, 3 H, Ar-CH3], 4.25 [s,
1 H, OH], 6.50 [s, 1 H, Ar-H]; 13C NMR (DCCl3) ppm 14.77
[Ar-CH3], 15.85 [Ar-CH3], 27.84 [(H3C)2], 30.88 [(H3C)2], 31.98
[ArC(CH3)2], 53.68 [CH2], 72.58 [OC(CH3)2], 117.56-146.68
7-Aceto-1,1,4,4-tetr a m eth yl-6-m eth oxy-3,4-d ih yd r o-1H-
2-ben zop yr a n (31). To a solution of 30 (0.989 g, 4.18 mmol),
acetyl chloride (0.74 mL, 10.0 mmol), and H3CNO2 (15 mL)