NO-Donor Phenols
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 10 2895
OCH2CH2O), 5.04 (s, 2H, OCH2O), 7.81 (s, 2H, C6H2), 9.92 (s,
1H, CHO); MS (CI) m/z 323 (M + 1)+.
reach room temperature and stirred for 1.5 h. The mixture was
poured into a saturated solution of NH4Cl and extracted with EtOAc.
The organic layers were washed with water and brine, dried, and
evaporated. The crude product so obtained was purified by flash
chromatography to give a colorless oil.
(6-((2-Methoxyethoxy)methoxy)-2,5,7,8-tetramethylchroman-
2-yl)methanol (27). Eluent PE/EtOAc 80/20; yield 84%; 1H NMR
(CDCl3) δ 1.22 (s, 3H, 2-CH3), 1.68-1.77 (m, 1H, 3-HaHb), 1.89
(s br, 1H, OH), 1.94-2.01 (m, 1H, 3-HaHb), 2.08 (s, 3H, ArCH3),
2.15 (s, 3H, ArCH3), 2.17 (s, 3H, ArCH3), 2.61-2.66 (m, 2H, 4-H2),
3.40 (s, 3H, OCH3), 3.56-3.67 (m, 4H, OCH2CH2O/2-CH2OH,
overlapped signals), 3.95-3.98 (m, 2H, OCH2CH2O), 4.95 (s, 2H,
OCH2O); MS (EI) m/z 324 (M)+. Anal. (C18H28O5) C, H, N.
General Procedure for 48-50. A solution of triethylphospho-
noacetate (2.25 mL, 13.8 mmol) in dry THF (18 mL) was slowly
added to a stirred solution of t-BuO-K+ (1.60 g, 14.3 mmol) in
dry THF (15 mL) kept under an inert atmosphere at -78 °C. Then
a solution of the appropriate aldehyde 45-47 (13.8 mmol) in dry
THF (20 mL) was slowly added. After 1 h the mixture was allowed
to reach room temperature and stirred for 1 h. The mixture was
poured into a saturated solution of NH4Cl and extracted with EtOAc.
The organic layers were washed with brine, dried, and evaporated.
Ethyl 3-(4-((tert-Butyl(dimethyl)silyl)oxy)phenyl)acrylate (48).
The crude product was purified by flash chromatography (PE/Et2O
95/5) to give the title compound as a colorless oil: yield 62%; 1H
NMR (CDCl3) δ 0.22 (s, 6H, Si(CH3)2), 0.99 (s, 9H, C(CH3)3),
3-(4-((tert-Butyl(dimethyl)silyl)oxy)phenyl)propan-1-ol (54).
1
Eluent Hex/EtOAc 95/5 f 80/20; yield 100%; H NMR (CDCl3)
3
1.34 (t, 3H, CH3CH2O, JHH ) 7.1 Hz), 4.25 (q, 2H, CH3CH2O,
δ 0.20 (s, 6H, Si(CH3)2), 1.00 (s, 9H, C(CH3)3), 1.40 (s br, 1H,
OH), 1.88 (m, 2H, CH2CH2CH2OH), 2.66 (t, 2H, CH2CH2CH2-
OH, 3JHH ) 7.4 Hz), 3.68 (t, 2H, CH2CH2CH2OH, 3JHH ) 6.4 Hz),
6.77 (d, 2H, AA′BB′ system), 7.06 (d, 2H, AA′BB′ system); MS
(EI) m/z 266 (M)+. Anal. (C15H26O2Si) C, H.
3
3JHH ) 7.1 Hz), 6.30 (d, 1H, COCHdCH, JHH ) 16.0 Hz), 6.83
(d, 2H, AA′BB′ system), 7.41 (d, 2H, AA′BB′ system), 7.63 (d,
3
1H, COCHdCH, JHH ) 16.0 Hz); MS (EI) m/z 306 (M)+. Anal.
(C17H26O3Si) C, H.
Ethyl 3-(3,5-Dimethoxy-4-((2-methoxyethoxy)methoxy)phen-
yl)acrylate (49). The crude product was purified by crystallization
from iPr2O to give the title compound as a white solid: yield 94%;
mp 51-54 °C (from iPr2O); 1H NMR (CDCl3) δ 1.34 (t, 3H, CH3-
3-(3,5-Dimethoxy-4-((2-methoxyethoxy)methoxy)phenyl)pro-
pan-1-ol (55). Because the product was unstable it was used directly
in the next synthetic step without further purification: yield 92%;
1H NMR (CDCl3) δ 1.76 (s br, 1H, OH), 1.87 (m, 2H, CH2CH2-
3
CH2O, JHH ) 7.1 Hz), 3.36 (s, 3H, OCH2CH2OCH3), 3.56 (m,
3
CH2OH), 2.64 (t, 2H, CH2CH2CH2OH, JHH ) 7.5 Hz), 3.37 (s,
2H, OCH2CH2O), 3.86 (s, 6H, OCH3), 3.99 (m, 2H, OCH2CH2O),
3H, OCH2CH2OCH3), 3.57 (m, 2H, OCH2CH2O), 3.68 (t, 2H, CH2-
3
4.26 (q, 2H, CH3CH2O, JHH ) 7.1 Hz), 5.23 (s, 2H, OCH2O),
3
CH2CH2OH, JHH ) 6.4 Hz), 3.81 (s, 6H, OCH3), 4.00 (m, 2H,
3
6.35 (d, 1H, COCHdCH, JHH ) 15.9 Hz), 6.75 (s, 2H, C6H2),
OCH2CH2O), 5.16 (s, 2H, OCH2O), 6.41 (s, 2H, C6H2); MS (EI)
7.60 (d, 1H, COCHdCH, 3JHH ) 15.9 Hz); MS (EI) m/z 340 (M)+.
Anal. (C17H24O7) C, H.
m/z 300 (M)+.
3-(3,5-Di-tert-butyl-4-((2-methoxyethoxy)methoxy)phenyl)-
propan-1-ol (56). Eluent Hex/EtOAc 80/20; yield 90%; 1H NMR
(CDCl3) δ 1.38 (s, 1H, OH), 1.43 (s, 18H, C(CH3)3), 1.87 (m, 2H,
Ethyl 3-(3,5-Di-tert-butyl-4-((2-methoxyethoxy)methoxy)phen-
yl)acrylate (50). The crude product was purified by flash chro-
matography (PE/Et2O 90/10) to give the title compound as pale
yellow oil: yield 84%; 1H NMR (CDCl3) δ 1.34 (t, 3H, CH3CH2O,
3JHH ) 7.1 Hz), 1.44 (s, 18H, C(CH3)3), 3.42 (s, 3H, OCH2CH2-
OCH3), 3.65 (m, 2H, OCH2CH2O), 3.99 (m, 2H, OCH2CH2O), 4.26
(q, 2H, CH3CH2O, 3JHH ) 7.1 Hz), 5.00 (s, 2H, OCH2O), 6.34 (d,
3
CH2CH2CH2OH), 2.62 (t, 2H, CH2CH2CH2OH, JHH ) 7.5 Hz),
3.42 (s, 3H, OCH2CH2OCH3), 3.63-3.71 (m, 4H), 3.98 (m, 2H)
(CH2CH2O/CH2CH2CH2OH overlapped signals), 4.98 (s, 2H,
OCH2O), 7.07 (s, 2H, C6H2); MS (EI) m/z 352 (M)+. Anal.
(C21H36O4) C, H.
3
1H, COCHdCH, JHH ) 16.0 Hz), 7.44 (s, 2H, C6H2), 7.64 (d,
General Procedure for 57-59 and 63. A solution of the
appropriate alcohol 54-56 and 27 (7.3 mmol) in dry THF (4 mL)
was slowly added to a suspension of NaH (60%, 0.44 g, 11.0 mmol)
in dry THF (4 mL), stirred under N2 at 0 °C. After 30 min 10
(2.69 g, 7.3 mmol) was added and the mixture was stirred at 30 °C
until the disappearance of the alcohol as shown by TLC. Then the
mixture was poured into a saturated solution of NH4Cl and extracted
with Et2O. The organic layers were washed with brine, dried, and
evaporated. The crude product was purified by flash chromatog-
raphy to give the title compound.
3
1H, COCHdCH, JHH ) 16.0 Hz); MS (EI) m/z 392 (M)+. Anal.
(C23H36O5) C, H.
General Procedure for 51-53. A solution of the appropriate
intermediate 48-50 (12.7 mmol) in EtOH (40 mL) was added to
a suspension of 10% palladium on charcoal catalyst (0.38 g) in
EtOH (20 mL), and the mixture was stirred under atmospheric
pressure of H2 for 3 h. Then the mixture was filtered through Celite
and evaporated. The product so obtained, a colorless oil, was used
in the next synthetic step without further purification.
Ethyl 3-(4-((tert-Butyl(dimethyl)silyl)oxy)phenyl)propanoate
(51). Yield 96%; 1H NMR (CDCl3) δ 0.19 (s, 6H, Si(CH3)2), 1.00
3-Benzenesulfonyl-4-(3-(4-(tert-butyl(dimethyl)silyl)oxy)phen-
1
3
yl)propoxy)furoxan (57). Eluent PE/EtOAc 95/5; yield 54%; H
(s, 9H, C(CH3)3), 1.24 (t, 3H, CH3CH2O, JHH ) 7.1 Hz), 2.59 (t,
3
3
NMR (CDCl3) δ 0.19 (s, 6H, Si(CH3)2), 0.98 (s, 9H, C(CH3)3),
2H, JHH ) 7.5 Hz), 2.89 (t, 2H, JHH ) 7.5 Hz) (COCH2CH2),
3
3
2.16 (m, 2H, CH2CH2CH2O), 2.74 (t, 2H, CH2CH2CH2O, JHH
)
4.13 (q, 2H, CH3CH2O, JHH ) 7.1 Hz), 6.76 (d, 2H, AA′BB′
3
system), 7.05 (d, 2H, AA′BB′ system); MS (EI) m/z 308 (M)+.
7.3 Hz), 4.40 (t, 2H, CH2CH2CH2O, JHH ) 6.4 Hz), 6.77 (d, 2H,
AA′BB′ system), 7.05 (d, 2H, AA′BB′ system), 7.60-8.09 (m, 5H,
C6H5SO2); MS (CI) m/z 491 (M + 1)+.
Ethyl 3-(3,5-Dimethoxy-4-((2-methoxyethoxy)methoxy)phen-
1
yl)propanoate (52). Yield 94%; H NMR (CDCl3) δ 1.25 (t, 3H,
3
3
3-Benzenesulfonyl-4-(3-(3,5-dimethoxy-4-((2-methoxyethoxy)-
CH3CH2O, JHH ) 7.1 Hz), 2.60 (t, 2H, JHH ) 7.5 Hz), 2.89 (t,
2H,3JHH ) 7.5 Hz) (COCH2CH2), 3.37 (s, 3H, OCH2CH2OCH3),
3.56 (m, 2H, OCH2CH2O), 3.86 (s, 6H, OCH3), 4.00 (m, 2H,
OCH2CH2O), 4.14 (q, 2H, CH3CH2O, 3JHH ) 7.1 Hz), 5.16 (s, 2H,
OCH2O), 6.41 (s, 2H, C6H2); MS (EI) m/z 342 (M)+.
methoxy)phenyl)propoxy)furoxan (58). Eluent CH2Cl2/EtOAc 95/
1
5; yield 52%; H NMR (CDCl3) δ 2.19 (m, 2H, CH2CH2CH2O),
3
2.77 (t, 2H, CH2CH2CH2O, JHH ) 7.2 Hz), 3.37 (s, 3H, OCH2-
CH2OCH3), 3.57 (m, 2H, OCH2CH2O), 3.82 (s, 6H, OCH3), 4.01
(m, 2H, OCH2CH2O), 4.43 (t, 2H, CH2CH2CH2O, 3JHH ) 6.3 Hz),
5.18 (s, 2H, OCH2O), 6.44 (s, 2H, C6H2), 7.56-8.09 (m, 5H, C6H5-
SO2); MS (EI) m/z 524 (M)+.
Ethyl 3-(3,5-Di-tert-butyl-4-((2-methoxyethoxy)methoxy)phen-
1
yl)propanoate (53). Yield 90%; H NMR (CDCl3) δ 1.23 (t, 3H,
3
CH3CH2O, JHH ) 7.1 Hz), 1.42 (s, 18H, C(CH3)3), 2.59 (t, 2H,
3JHH ) 7.5 Hz), 2.88 (t, 2H, 3JHH ) 7.5 Hz) (COCH2CH2), 3.42 (s,
3H, OCH2CH2OCH3), 3.66 (m, 2H, OCH2CH2O), 3.98 (m, 2H,
OCH2CH2O), 4.14 (q, 2H, CH3CH2O, 3JHH ) 7.1 Hz), 4.97 (s, 2H,
OCH2O), 7.07 (s, 2H, C6H2); MS (EI) m/z 394 (M)+.
3-Benzenesulfonyl-4-(3-(3,5-di-tert-butyl-4-((2-methoxyethoxy)-
methoxy)phenyl)propoxy)furoxan (59). Eluent PE/EtOAc 9/1;
1
yield 54%; H NMR (CDCl3) δ 1.42 (s, 18H, C(CH3)3), 2.17 (m,
3
2H, CH2CH2CH2O), 2.73 (t, 2H, CH2CH2CH2O, JHH ) 7.2 Hz),
General Procedure for 27 and 54-56. A solution of the
appropriate ethyl ester 26 and 51-53 (10.2 mmol) in dry THF (25
mL) was slowly added to a suspension, stirred under N2 at 0 °C,
of LiAlH4 (0.41 g, 10.2 mmol). Then the mixture was allowed to
3.42 (s, 3H, OCH2CH2OCH3), 3.65 (m, 2H, OCH2CH2O), 3.99 (m,
2H, OCH2CH2O), 4.42 (t, 2H, CH2CH2CH2O, 3JHH ) 6.4 Hz), 4.99
(s, 2H, OCH2O), 7.06 (s, 2H, C6H2), 7.59-8.10 (m, 5H, C6H5-
SO2); MS (EI) m/z 576 (M)+.